AAAS

UniProt ID: Q9NRG9
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

AAAS encodes ALADIN, a WD-repeat scaffold nucleoporin of the nuclear pore complex. ALADIN is anchored at the nuclear envelope through NDC1 and contributes to normal NPC-associated nucleocytoplasmic transport, especially in tissues affected by triple-A syndrome such as adrenal, gastrointestinal, and neural systems. In mitosis, ALADIN also localizes to spindle structures and helps spatially regulate inactive Aurora A and downstream spindle factors, supporting robust spindle formation and chromosome alignment.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005643 nuclear pore
IBA
GO_REF:0000033 		ACCEPT
Summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
Reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
Supporting Evidence:
PMID:12730363
ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0006913 nucleocytoplasmic transport
IBA
GO_REF:0000033 		ACCEPT
Summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
Reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
Supporting Evidence:
PMID:12730363
We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
PMID:27016207
The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.
GO:0000922 spindle pole
IEA
GO_REF:0000044 		ACCEPT
Summary: ALADIN localizes to mitotic spindle structures, including the spindle pole, in the AURKA/spindle study.
Reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
Supporting Evidence:
PMID:26246606
Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
PMID:26246606
ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
GO:0005635 nuclear envelope
IEA
GO_REF:0000044 		ACCEPT
Summary: Nuclear envelope/nuclear membrane localization is consistent with ALADIN being an NPC nucleoporin anchored through NDC1.
Reason: This cellular component is well supported by ALADIN-specific localization and anchoring evidence. For the HPA-derived nuclear membrane row, the term is less specific than nuclear pore but still consistent with the NPC location at the nuclear envelope.
Supporting Evidence:
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0005643 nuclear pore
IEA
GO_REF:0000044 		ACCEPT
Summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
Reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
Supporting Evidence:
PMID:12730363
ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0005635 nuclear envelope
IDA
PMID:24315095
Integrated structural analysis of the human nuclear pore com... 		ACCEPT
Summary: The original structural NPC-scaffold source has only abstract text available locally, but independent ALADIN-specific evidence supports nuclear-envelope/NPC localization.
Reason: Retain the nuclear envelope annotation because ALADIN is directly shown to be anchored in the nuclear envelope via NDC1. The unavailable original full text limits direct assessment of the 2013 structural study details, so the review also relies on ALADIN-specific localization evidence.
Supporting Evidence:
PMID:24315095
The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules.
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005643 nuclear pore
NAS
PMID:24315095
Integrated structural analysis of the human nuclear pore com... 		ACCEPT
Summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
Reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
Supporting Evidence:
PMID:12730363
ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0006913 nucleocytoplasmic transport
NAS
PMID:27016207
The Structure Inventory of the Nuclear Pore Complex. 		ACCEPT
Summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
Reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
Supporting Evidence:
PMID:12730363
We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
PMID:27016207
The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: The HPA-derived nucleoplasm signal is plausible for an NPC-associated protein but is less specific than nuclear pore/nuclear envelope localization.
Reason: AAAS should primarily be represented as a nuclear pore/nuclear envelope component. Nucleoplasm localization may reflect immunofluorescence signal or cell-state context and is not the best descriptor of the core site of action.
Supporting Evidence:
PMID:12730363
ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
GO:0031965 nuclear membrane
IDA
GO_REF:0000052 		ACCEPT
Summary: Nuclear envelope/nuclear membrane localization is consistent with ALADIN being an NPC nucleoporin anchored through NDC1.
Reason: This cellular component is well supported by ALADIN-specific localization and anchoring evidence. For the HPA-derived nuclear membrane row, the term is less specific than nuclear pore but still consistent with the NPC location at the nuclear envelope.
Supporting Evidence:
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0005515 protein binding
IPI
PMID:28811369
Obesity-associated gene TMEM18 has a role in the central con... 		REMOVE
Summary: This protein binding row comes from a TMEM18 study that reports interaction with NPC components. It does not define a specific AAAS molecular function.
Reason: GO:0005515 protein binding is too generic for curation and the source is primarily about TMEM18 biology. The finding may identify AAAS as an NPC component/interactor, but that context is already captured by nuclear pore and nucleocytoplasmic transport annotations.
Supporting Evidence:
PMID:28811369
We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex.
GO:0005515 protein binding
IPI
PMID:27754849
Identification of a novel putative interaction partner of th... 		REMOVE
Summary: The PGRMC2 interaction with ALADIN is experimentally supported, but protein binding is uninformative as a GO molecular-function annotation.
Reason: The interaction should be retained as biological evidence in the notes/reference findings, not as the generic GO:0005515 term. No more specific AAAS molecular-function term is supported strongly enough from this interaction alone.
Supporting Evidence:
PMID:27754849
In an attempt to identify new interaction partners of ALADIN, co-IP analyses showed that PGRMC2 precipitated with ALADIN.
GO:0005635 nuclear envelope
IDA
PMID:27754849
Identification of a novel putative interaction partner of th... 		ACCEPT
Summary: ALADIN is observed at the nuclear envelope/perinuclear region in adrenal-cell interaction experiments with PGRMC2.
Reason: This is consistent with the core NPC/nuclear-envelope localization of AAAS. The PGRMC2 paper supports nuclear-envelope localization and an interaction context, but it should not be inflated into a specific transport or steroidogenesis GO process for AAAS.
Supporting Evidence:
PMID:27754849
We detected that PGRMC2 co-localises with ALADIN and with different FG-repeat NUPs [stained with anti-NPC proteins (mAb414)] to the nuclear envelope and the perinuclear ER.
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0000922 spindle pole
IDA
PMID:26246606
The nucleoporin ALADIN regulates Aurora A localization to en... 		ACCEPT
Summary: ALADIN localizes to mitotic spindle structures, including the spindle pole, in the AURKA/spindle study.
Reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
Supporting Evidence:
PMID:26246606
Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
PMID:26246606
ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
GO:0001578 microtubule bundle formation
IMP
PMID:26246606
The nucleoporin ALADIN regulates Aurora A localization to en... 		KEEP AS NON CORE
Summary: ALADIN depletion produces shorter, less robust spindles and affects spindle microtubule organization.
Reason: The phenotype supports a role in spindle organization, but microtubule bundle formation is a less direct and less informative description than mitotic spindle assembly/AURKA localization. Keep the row as non-core supporting phenotype rather than the main process term.
Supporting Evidence:
PMID:26246606
Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
PMID:26246606
ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
GO:0072686 mitotic spindle
IDA
PMID:26246606
The nucleoporin ALADIN regulates Aurora A localization to en... 		ACCEPT
Summary: ALADIN localizes to mitotic spindle structures, including the mitotic spindle, in the AURKA/spindle study.
Reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
Supporting Evidence:
PMID:26246606
Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
PMID:26246606
ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
GO:0090307 mitotic spindle assembly
IMP
PMID:26246606
The nucleoporin ALADIN regulates Aurora A localization to en... 		ACCEPT
Summary: ALADIN is required for robust mitotic spindle formation and timely chromosome alignment through spatial regulation of Aurora A and associated spindle factors.
Reason: This is directly supported by depletion experiments in human and Drosophila cells and by phenotypes in triple-A patient fibroblasts. It should be retained as a well-supported AAAS biological process.
Supporting Evidence:
PMID:26246606
Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
PMID:26246606
ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
GO:0005643 nuclear pore
IDA
PMID:12730363
The nuclear pore complex protein ALADIN is mislocalized in t... 		ACCEPT
Summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
Reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
Supporting Evidence:
PMID:12730363
ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
PMID:19782045
We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells. 		MARK AS OVER ANNOTATED
Summary: AAAS was detected in a high-throughput membrane proteomics study, but generic membrane localization is much less informative than nuclear envelope/nuclear pore.
Reason: The term is not strictly false because the NPC is embedded in the nuclear envelope, but this HDA row loses the important nuclear-pore context and the source study includes many proteins predicted to be transiently associated with membranes.
Supporting Evidence:
PMID:19946888
The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
GO:0005634 nucleus
HDA
PMID:21630459
Proteomic characterization of the human sperm nucleus. 		MARK AS OVER ANNOTATED
Summary: AAAS was detected in a sperm nucleus proteomics data set, but generic nucleus localization is broader than the established nuclear pore/nuclear envelope site.
Reason: The nucleus term is broadly compatible with an NPC protein but over-generalizes the curated AAAS localization. Nuclear pore and nuclear envelope should be preferred for functional interpretation.
Supporting Evidence:
PMID:21630459
With this approach, 403 different proteins have been identified from the isolated sperm nuclei.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-1176059 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-165043 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-165047 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-170796 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-180622 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-192627 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-192925 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-2990880 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-2990882 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-3000348 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-3000399 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-3000411 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4551649 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4551679 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4570493 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4615872 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4615987 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-4655355 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-5228508 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-5228523 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-5252041 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-5661474 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-6783483 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-75096 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-75097 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-75098 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-9614367 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-9614369 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0005635 nuclear envelope
TAS
Reactome:R-HSA-9708889 		ACCEPT
Summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
Reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
Supporting Evidence:
PMID:19782045
Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
GO:0006913 nucleocytoplasmic transport
IDA
PMID:12730363
The nuclear pore complex protein ALADIN is mislocalized in t... 		ACCEPT
Summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
Reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
Supporting Evidence:
PMID:12730363
We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
PMID:27016207
The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.
GO:0046822 regulation of nucleocytoplasmic transport
NAS
PMID:12730363
The nuclear pore complex protein ALADIN is mislocalized in t... 		ACCEPT
Summary: The original ALADIN disease-mutant study explicitly proposed a regulatory role in nucleocytoplasmic transport.
Reason: This term is a conservative way to capture ALADIN as an NPC-associated regulator/support factor rather than a transport receptor or cargo-specific transporter. It is preferable to adding broad protein transport from the PN projection.
Supporting Evidence:
PMID:12730363
We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
PMID:27016207
The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.

Core Functions

ALADIN is a scaffold nucleoporin of the nuclear pore complex at the nuclear envelope. Its NDC1-dependent NPC anchoring supports normal NPC-associated nucleocytoplasmic transport; disease-associated variants commonly fail to target to NPCs, linking loss of NPC integration to triple-A syndrome biology.

Directly Involved In:
nucleocytoplasmic transport regulation of nucleocytoplasmic transport
Cellular Locations:
nuclear envelope
In Complex:
nuclear pore
Supporting Evidence:
  • PMID:12730363
    A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm.
  • PMID:19782045
    Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
  • file:human/AAAS/AAAS-deep-research-falcon.md
    Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate.

During mitosis, ALADIN acts as a spatial regulator of Aurora A localization and associated spindle factors, supporting robust mitotic spindle formation and timely chromosome alignment.

Directly Involved In:
mitotic spindle assembly
Cellular Locations:
mitotic spindle spindle pole
Supporting Evidence:
  • PMID:26246606
    Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
  • PMID:26246606
    ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
  • file:human/AAAS/AAAS-deep-research-falcon.md
    Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
PMID:24315095
Integrated structural analysis of the human nuclear pore complex scaffold.
  • The human NPC scaffold is a multi-nucleoporin assembly mediating nucleocytoplasmic exchange.
    "The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules."
PMID:27016207
The Structure Inventory of the Nuclear Pore Complex.
  • NPCs are the principal gateway for nuclear-cytoplasmic exchange.
    "The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope."
  • NPCs are built from about 30 nucleoporins and positioned in nuclear-envelope openings.
    "Analyzing the protein composition of NPCs from various eukaryotic origin reveals that they all share a set of ~30 nucleoporins (Nups)."
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
PMID:28811369
Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.
  • TMEM18 interacts with nuclear pore complex components, but this does not establish a specific AAAS molecular function beyond a generic interaction.
    "We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex."
PMID:27754849
Identification of a novel putative interaction partner of the nucleoporin ALADIN.
  • PGRMC2 co-immunoprecipitates with ALADIN in adrenal cell models.
    "In an attempt to identify new interaction partners of ALADIN, co-IP analyses showed that PGRMC2 precipitated with ALADIN."
  • ALADIN and PGRMC2 are associated near the nuclear envelope/perinuclear ER.
    "Taken together, our results in immunofluorescence microscopy using different ALADIN and PGRMC2 adrenal cell expression systems provide a basis for future research of how ALADIN and PGRMC2 possibly associate in a complex close to the nuclear envelope, and what the effects on steroidogenesis of this association would be."
PMID:26246606
The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation.
  • ALADIN regulates Aurora A localization during mitotic spindle formation.
    "In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A."
  • ALADIN loss slows spindle assembly and chromosome alignment.
    "Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment."
  • ALADIN interacts with inactive Aurora A and is recruited to spindle poles after Aurora A inhibition.
    "ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition."
PMID:12730363
The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.
  • ALADIN localizes to nuclear pore complexes.
    "ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport."
  • Patient mutations disrupt NPC targeting while leaving gross NPC structure intact.
    "A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm."
  • The authors proposed a regulatory role in nucleocytoplasmic transport.
    "We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues."
PMID:19946888
Defining the membrane proteome of NK cells.
  • AAAS was identified in a high-throughput membrane proteomics data set; the paper cautions that many identified proteins may only be transiently membrane-associated.
    "The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes."
PMID:21630459
Proteomic characterization of the human sperm nucleus.
  • AAAS was detected in an isolated sperm nucleus proteomics data set.
    "With this approach, 403 different proteins have been identified from the isolated sperm nuclei."
Reactome:R-HSA-1176059
Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleus
Reactome:R-HSA-165043
Rev multimer-bound HIV mRNA:Crm1:Ran:GTP complex associates with the NPC
Reactome:R-HSA-165047
Translocation of nuclear RNA transport complex to cytoplasm
Reactome:R-HSA-170796
NPC transports GCK1:GCKR from cytosol to nucleoplasm
Reactome:R-HSA-180622
Vpr binds nucleoporins
Reactome:R-HSA-192627
Viral mRNA Export
Reactome:R-HSA-192925
Export of Spliced Viral mRNA
Reactome:R-HSA-2990880
NEK6/NEK7 phosphorylates NUP98
Reactome:R-HSA-2990882
CDK1 phosphorylates NUP98
Reactome:R-HSA-3000348
RANBP2 SUMOylates SP100 with SUMO2
Reactome:R-HSA-3000399
RANBP2 SUMOylates SP100 with SUMO1
Reactome:R-HSA-3000411
RANBP2 SUMOylates PML with SUMO2
Reactome:R-HSA-4551649
RANBP2 SUMOylates RANBP2 with SUMO1
Reactome:R-HSA-4551679
RANBP2 SUMOylates RANBP2 with SUMO2
Reactome:R-HSA-4570493
RANBP2 (NUP358) SUMOylates HNRNPC with SUMO1
Reactome:R-HSA-4615872
RANBP2 SUMOylates HDAC4 with SUMO1
Reactome:R-HSA-4615987
RANBP2 SUMOylates HDAC4 with SUMO2,3
Reactome:R-HSA-4655355
RANBP2 SUMOylates CDCA8 (Borealin) and PIAS3 SUMOylates AURKB (Aurora-B)
Reactome:R-HSA-5228508
RANBP2 SUMOylates PML with SUMO1
Reactome:R-HSA-5228523
RANBP2 SUMOylates MDM2 with SUMO1
Reactome:R-HSA-5252041
NPC transports Hikeshi:HSP70s:ATP from cytosol to nucleoplasm
Reactome:R-HSA-5661474
Defective NPC does not transport GCK1:GKRP from cytosol to nucleoplasm
Reactome:R-HSA-6783483
tRNA:XPOT:RAN:GTP translocates from the nucleus to the cytosol
Reactome:R-HSA-75096
Docking of the TAP:EJC Complex with the NPC
Reactome:R-HSA-75097
Transport of the export-competent mRNP complex through the NPC
Reactome:R-HSA-75098
mRNP complex dissociates from cytosolic face of NPC
Reactome:R-HSA-9614367
HCMV Nuclear Pore Docking
Reactome:R-HSA-9614369
Transport of HCMV DNA Into the Nucleus
Reactome:R-HSA-9708889
SARS-CoV-2 6 binds NUP98:RAE1 within NPC
PMID:11062474
Mutant WD-repeat protein in triple-A syndrome.
  • AAAS encodes ALADIN, a WD-repeat protein mutated in triple-A syndrome.
    "The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome."
  • Expression in affected neuroendocrine and cerebral structures supports developmental and neurological relevance.
    "The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems."
PMID:11159947
Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.
  • Loss-of-function AAAS mutations cause triple-A syndrome.
    "In nine triple A syndrome patients eight different homozygous and compound heterozygous mutations were found in this gene, most of them leading to a truncated protein suggesting loss of function."
  • AAAS is expressed in neuroendocrine and gastrointestinal structures affected in disease.
    "RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple A syndrome, supporting the hypothesis that mutations in this triple A syndrome gene (AAAS) are responsible for the disease."
PMID:16022285
Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS.
  • AAAS has a shorter splice variant that remains broadly expressed.
    "RT-PCR analysis in our work revealed that AAAS-v2 and AAAS-v1 were ubiquitously detected in human multiple tissue cDNA (MTC) panels (CLONTECH)."
PMID:19782045
The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope.
  • ALADIN is anchored in the NPC through NDC1.
    "We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC."
  • Loss of ALADIN integration into the NPC is disease-relevant.
    "The loss of integration of ALADIN in the NPC is a main pathogenetic aspect for the development of the triple A syndrome and suggests that the interaction between ALADIN and NDC1 may be involved in the pathogenesis of the disease."
file:human/AAAS/AAAS-uniprot.txt
UniProtKB Q9NRG9 AAAS/ALADIN record
  • UniProt summarizes ALADIN as an NPC protein with roles in AURKA/NUMA1 localization and spindle formation.
    "Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment"
  • UniProt records the nuclear pore complex, spindle pole, and nuclear envelope locations.
    "Nucleus, nuclear pore complex"
file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
Proteostasis PN projected candidate additions for AAAS
  • PN projection suggests GO:0015031 protein transport from Nuclear proteostasis | Protein transport, but this is a broad class-level projection and is not added as a new AAAS annotation in this conservative review.
    "AAAS GO:0015031 protein transport new_to_goa ok_for_propagation_to_go nuclear_proteostasis.yaml Nuclear proteostasis|Protein transport Nuclear proteostasis|Protein transport|Nuclear pore complex"
file:human/AAAS/AAAS-deep-research-falcon.md
Falcon deep research report for human AAAS
  • Falcon deep research summarizes AAAS/ALADIN as an NPC/nuclear-envelope scaffold whose localization is NDC1-dependent.
    "ALADIN localizes to the **NPC/nuclear envelope**; proper NE/NPC targeting is **NDC1-dependent**."
  • Falcon deep research treats ALADIN as a scaffold/selective transport regulator rather than an enzyme or small-molecule transporter.
    "Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate."

Suggested Questions for Experts

Q: Should AAAS be annotated to a more specific nuclear protein import/export term only if future gene-level evidence identifies affected protein cargos, rather than adding the broad PN-projected GO:0015031 protein transport?

Suggested experts: Cronshaw JM, Matunis MJ, Kind B, Huebner A

Q: Is the ALADIN-PGRMC2 association functionally upstream of adrenal steroidogenesis in vivo, or should it remain an interaction note without a GO process annotation?

Suggested experts: Juehlen R, Koehler K, Huebner A

Suggested Experiments

Experiment: Perform quantitative nuclear/cytoplasmic proteomics or live import/export reporter assays in AAAS-null and rescue human adrenal/neural cell models, with cargo-level validation for candidate proteins.

Hypothesis: ALADIN loss selectively alters nuclear import or export of stress-response or DNA-repair proteins in adrenal and neural cell types.

Type: nucleocytoplasmic transport assay

Experiment: Compare steroidogenic enzyme activity, PGRMC2 localization, and CYP-dependent steroid output in AAAS knockout, NDC1-anchoring-defective rescue, and wild-type rescue adrenocortical cells.

Hypothesis: The ALADIN-PGRMC2 interaction has a specific steroidogenic consequence rather than representing proximity at the perinuclear ER/NPC.

Type: functional rescue and steroidogenesis assay

Deep Research

Falcon

(AAAS-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 29 citations 2 artifacts 2026-06-03T09:06:30.201781
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000030 Figure 4 in the document provides the requested visual data related to NDC1 variants. - **Panel A** displays immunofluorescence ima (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human AAAS (UniProt Q9NRG9) / ALADIN

Scope and target verification

This report concerns human AAAS, which encodes the nucleoporin ALADIN (UniProt accession Q9NRG9), a 546–amino-acid WD-repeat protein localized to the nuclear pore complex (NPC); this identity is consistently stated in recent peer-reviewed literature and matches the UniProt target context provided. (ruizbabot2023generationofglucocorticoidproducing pages 12-14, hasenmajer2023rareformsof pages 9-10)

Executive summary (current understanding)

AAAS/ALADIN is best understood as a non-enzymatic WD-repeat scaffold nucleoporin that supports selective nucleocytoplasmic trafficking of specific protein cargoes and/or regulators at the NPC, with downstream consequences for DNA repair capacity, nuclear protection from oxidative damage, and adrenal steroidogenic signaling. Pathogenic biallelic variants cause triple A (Allgrove) syndrome, classically featuring alacrima, achalasia, and primary adrenal insufficiency, often with neurological/autonomic involvement. (cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14, smits2024biallelicndc1variants pages 8-10)

1) Key concepts and definitions (functional annotation focus)

1.1 Nuclear pore complex (NPC) context and ALADIN as a nucleoporin scaffold

ALADIN is described as a WD-repeat nucleoporin localized to the NPC, where WD repeats (seven described in recent sources) are interpreted as forming a protein–protein interaction scaffold rather than conferring catalytic activity. (ruizbabot2023generationofglucocorticoidproducing pages 12-14, ruizbabot2023generationofglucocorticoidproducing pages 3-4)

Functional definition (gene product role): rather than transporting metabolites or catalyzing reactions, ALADIN’s primary functional annotation is NPC-associated regulation/enablement of selective nuclear import/export of specific proteins, which can produce tissue-specific phenotypes when disrupted. (cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

1.2 Established localization and anchoring mechanism: dependence on NDC1

A major advance in current mechanistic understanding is the clear emphasis that ALADIN’s correct localization at the NPC/nuclear envelope is NDC1-dependent. Recent work summarizes that ALADIN is anchored via the transmembrane nucleoporin NDC1 (rather than POM121/GP210) and that disruption of this interaction reduces ALADIN nuclear-envelope recruitment. (smits2024biallelicndc1variants pages 11-12, smits2024biallelicndc1variants pages 8-10)

A 2024 study in Human Genetics and Genomics Advances provides direct cellular evidence: fibroblasts carrying pathogenic NDC1 variants show reduced ALADIN localization to the nuclear envelope and a measurable defect in post-mitotic NPC insertion/assembly. (smits2024biallelicndc1variants media 042ddde5, smits2024biallelicndc1variants pages 5-7)

1.3 Interaction partners and affected cargoes: DNA repair proteins and ferritin

Recent reviews and mechanistic syntheses highlight selective nuclear import failure affecting:
- DNA ligase I and aprataxin (DNA single-strand break repair proteins). (braun2026pathologiesatthe pages 10-12, cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14)
- Ferritin heavy chain (FTH1), which is discussed as protective against nuclear oxidative damage; impairment of its nuclear import is used to support an oxidative-damage mechanism. (braun2026pathologiesatthe pages 10-12, smits2024biallelicndc1variants pages 8-10, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

Collectively, these findings frame ALADIN as an NPC component required for nuclear access of genome-maintenance and oxidative-protection factors in relevant cellular contexts. (braun2026pathologiesatthe pages 10-12, cehic2024veryearlyand pages 8-9)

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 2024: Expansion of the ALADIN–NDC1 axis and “triple A–like” disease mechanisms

Smits et al. (Oct 2024; https://doi.org/10.1016/j.xhgg.2024.100327) report biallelic NDC1 variants that interfere with ALADIN binding and associate with neuropathy and a triple A–like syndrome, underscoring that disruption of ALADIN recruitment can arise from genes beyond AAAS itself. (smits2024biallelicndc1variants pages 8-10, smits2024biallelicndc1variants pages 5-7)

Quantitative cellular evidence in this work includes a reduction in CDT1-positive NPC density in patient cells versus controls (mean 4.05 vs 4.58 pore/mm²; p < 0.002), supporting impaired post-mitotic NPC insertion/assembly. (smits2024biallelicndc1variants pages 5-7)

2.2 2023: Patient adrenal tissue provides a mechanistic bridge to steroidogenesis (SCARB1/PKA)

Bitetto et al. (Jun 2023; https://doi.org/10.1186/s13023-023-02763-w) examined postmortem adrenal tissue from an AAAS-mutant patient and reported:
- Reduced ALADIN in total lysate and membrane fraction with slight cytosolic increase (consistent with altered localization/fractionation).
- Reduced SCARB1 transcript, reduced MC2R (ACTH receptor) immunoreactivity, and phospho-PKA mislocalization (reduced nuclear, increased cytosolic fractions), suggesting impaired ACTH/cAMP signaling and transcriptional activation of steroidogenic pathways. (bitetto2023scarb1downregulationin pages 4-6, bitetto2023scarb1downregulationin pages 6-8, bitetto2023scarb1downregulationin pages 1-2)

These findings provide a concrete, human-tissue-supported mechanism connecting an NPC protein defect to adrenal steroidogenic failure. (bitetto2023scarb1downregulationin pages 6-8)

2.3 2023: Human iPSC-derived steroidogenic cells as a functional AAAS disease model

Ruiz-Babot et al. (Nov 2023; https://doi.org/10.1016/j.crmeth.2023.100627) developed human pluripotent stem cell–derived steroidogenic cells and used CRISPR-engineered AAAS knockout and an AAAS truncation model to recapitulate triple A adrenal insufficiency phenotypes. (ruizbabot2023generationofglucocorticoidproducing pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 21-23)

In this system, AAAS/ALADIN loss is associated with reduced steroid output: KO and mutant lines secrete significantly lower cortisol, cortisone, corticosterone, and aldosterone than controls (measured by ELISA and LC–MS), and a block at 11β-hydroxylation (CYP11B enzymes) is described as a mechanistic bottleneck. (ruizbabot2023generationofglucocorticoidproducing pages 12-14)

3) Cellular localization and where AAAS/ALADIN carries out its function

The functional site of action is the nuclear envelope at nuclear pore complexes, where ALADIN is recruited/anchored by NDC1, and where its loss or mislocalization is repeatedly emphasized as a pathogenic feature in triple A syndrome. (smits2024biallelicndc1variants pages 11-12, cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

A key visual demonstration of ALADIN’s NPC localization dependence is shown in Smits et al. 2024 (Figure 4), where immunofluorescence indicates reduced ALADIN nuclear-envelope recruitment in patient fibroblasts with NDC1 variants, along with quantification of reduced post-mitotic NPC density. (smits2024biallelicndc1variants media 042ddde5)

4) Pathways and mechanistic models linking AAAS variants to disease

4.1 Nucleocytoplasmic transport and genome maintenance (DNA repair protein import)

A widely cited mechanistic model is that ALADIN disruption causes selective nuclear import defects for specific proteins (DNA ligase I, aprataxin), plausibly elevating DNA damage burden in susceptible tissues. (braun2026pathologiesatthe pages 10-12, cehic2024veryearlyand pages 1-3)

4.2 Redox/oxidative stress vulnerability and nuclear protection

ALADIN dysfunction is repeatedly connected to oxidative stress susceptibility, supported by discussions of ferritin heavy-chain nuclear import defects and increased cellular reactive oxygen species in patient-derived contexts. (cehic2024veryearlyand pages 8-9, cehic2024veryearlyand pages 5-6, smits2024biallelicndc1variants pages 8-10)

4.3 Adrenal steroidogenesis and ACTH resistance (SCARB1/PKA/MC2R)

Two complementary 2023 lines of evidence connect AAAS/ALADIN to adrenal dysfunction:
1) Human adrenal tissue findings show reduced SCARB1 and MC2R and altered phospho-PKA localization, suggesting impaired ACTH/cAMP/PKA-driven transcriptional control of steroidogenic capacity. (bitetto2023scarb1downregulationin pages 6-8, bitetto2023scarb1downregulationin pages 1-2)
2) iPSC-derived steroidogenic cell modeling shows reduced secretion of multiple adrenal steroids (glucocorticoids and mineralocorticoids) in AAAS-deficient cells. (ruizbabot2023generationofglucocorticoidproducing pages 12-14, ruizbabot2023generationofglucocorticoidproducing pages 3-4)

Together, these place AAAS/ALADIN within a mechanistic chain: NPC disruption → altered nuclear signaling/transport → dysregulated steroidogenic gene expression and enzymatic steps → adrenal insufficiency. (bitetto2023scarb1downregulationin pages 6-8, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

5) Current applications and real-world implementations

5.1 Clinical genetics and differential diagnosis

Genetic testing for AAAS is central to confirming triple A syndrome, and recent clinical reviews emphasize that neurological involvement can be common and heterogeneous, making molecular confirmation important for management and family counseling. (cehic2024veryearlyand pages 1-3, hasenmajer2023rareformsof pages 9-10)

Smits et al. (2024) extends real-world implementation by highlighting that “triple A–like” phenotypes can result from NDC1 variants that disrupt ALADIN recruitment, implying that patients negative for AAAS mutations may warrant evaluation of ALADIN-anchoring machinery. (smits2024biallelicndc1variants pages 8-10)

5.2 Disease modeling for mechanism discovery and therapeutic testing

The 2023 iPSC-derived steroidogenic cell system provides a practical platform for studying AAAS-associated adrenal insufficiency and for testing interventions in a human-relevant context, addressing limitations of mouse models that may not recapitulate the full human phenotype. (ruizbabot2023generationofglucocorticoidproducing pages 15-16, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

5.3 Mechanism-guided therapeutic hypotheses (oxidative stress modulation)

Recent clinical-review literature references antioxidant approaches (e.g., N-acetylcysteine) as exploratory strategies consistent with oxidative stress models, although robust clinical trial evidence is not established in the provided sources. (cehic2024veryearlyand pages 5-6)

6) Expert opinions and authoritative analyses

6.1 What is well supported vs. still uncertain

Authoritative recent reviews emphasize that although ALADIN’s precise molecular function is not fully resolved, convergent evidence supports roles in nucleocytoplasmic transport of selected proteins, redox homeostasis, and adrenal steroidogenesis—with mislocalization of mutant ALADIN from NPC to cytoplasm recurring as a key pathogenic theme. (cehic2024veryearlyand pages 1-3, hasenmajer2023rareformsof pages 9-10, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

7) Relevant statistics and data (recent studies)

7.1 Clinical feature frequencies (2024 review/case review synthesis)

Cehic et al. (Sep 2024; https://doi.org/10.3389/fendo.2024.1431383) summarize clinical frequencies:
- Alacrima: >90% (also stated as “above 90%”).
- Achalasia: 75–85%.
- Primary adrenal insufficiency: almost 85%.
- Complete triad: about 70%.
- Neurological involvement: about two-thirds (also described as ~60% in the same review). (cehic2024veryearlyand pages 1-3, cehic2024veryearlyand pages 4-5)

7.2 Genetics and case-definition statistics (2023 review)

Hasenmajer et al. (Feb 2023; https://doi.org/10.1007/s11154-023-09784-7) report:
- Fewer than 50 families described (reflecting rarity).
- AAAS variants in ~90% of patients.
- A literature review recorded 74 AAAS variants.
- Achalasia in most cohorts around 75–85%, with onset ranging from months to adolescence. (hasenmajer2023rareformsof pages 9-10, hasenmajer2023rareformsof pages 8-9)

7.3 Quantitative cell biology (2024 mechanistic genetics)

Smits et al. (Oct 2024; https://doi.org/10.1016/j.xhgg.2024.100327) report reduced post-mitotic NPC density in patient fibroblasts (4.05 vs 4.58 pore/mm²; p < 0.002) and show reduced ALADIN nuclear-envelope localization in patient cells. (smits2024biallelicndc1variants pages 5-7, smits2024biallelicndc1variants media 042ddde5)

Evidence synthesis table

The following table summarizes key functional-annotation facts, mechanisms, and recent sources.

Aspect Key findings for human AAAS/ALADIN (UniProt Q9NRG9) Strongest evidence type Representative recent source(s)
Verified molecular identity AAAS encodes ALADIN, a 546-aa WD-repeat nucleoporin of the nuclear pore complex (NPC); recent reviews/methods papers describe 7 WD repeats and broad expression with enrichment in adrenal/pituitary/CNS/GI-related tissues, matching the UniProt human target Q9NRG9 rather than another gene symbol usage (hasenmajer2023rareformsof pages 9-10, ruizbabot2023generationofglucocorticoidproducing pages 12-14) Review; iPSC/model background Hasenmajer et al., Feb 2023, Rev Endocr Metab Disord, https://doi.org/10.1007/s11154-023-09784-7 (hasenmajer2023rareformsof pages 9-10); Ruiz-Babot et al., Nov 2023, Cell Reports Methods, https://doi.org/10.1016/j.crmeth.2023.100627 (ruizbabot2023generationofglucocorticoidproducing pages 12-14)
Primary localization ALADIN localizes to the NPC/nuclear envelope; proper NE/NPC targeting is NDC1-dependent. NDC1 variants that disrupt the ALADIN-binding region reduce ALADIN recruitment to the NE, and ALADIN is reported as anchored via NDC1 rather than POM121/GP210 (smits2024biallelicndc1variants pages 11-12, smits2024biallelicndc1variants pages 5-7, smits2024biallelicndc1variants media 042ddde5) Structural/cell assay with patient fibroblasts Smits et al., Oct 2024, Hum Genet Genomics Adv, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 11-12, smits2024biallelicndc1variants pages 5-7, smits2024biallelicndc1variants media 042ddde5)
Key interaction partner: NDC1 NDC1 is the principal membrane anchor recruiting ALADIN to the NPC; structural modeling places NDC1 C-terminal residues in direct interface with ALADIN, and disease-associated NDC1 alleles impair ALADIN localization and NPC assembly/post-mitotic insertion (smits2024biallelicndc1variants pages 8-10, smits2024biallelicndc1variants pages 5-7) Structural modeling + patient fibroblast assay Smits et al., Oct 2024, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10, smits2024biallelicndc1variants pages 5-7)
Other NPC-related partners Recent literature also places ALADIN in a network including NUP155 in addition to NDC1; proteomic/NPC studies support ALADIN as a bona fide NPC component mislocalized in triple A syndrome (smits2024biallelicndc1variants pages 8-10, braun2026pathologiesatthe pages 23-24) Review; NPC interaction mapping Smits et al., Oct 2024, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10); Braun et al., Apr 2026, https://doi.org/10.1007/s00018-026-06220-2 (braun2026pathologiesatthe pages 23-24)
Cargoes/processes affected: DNA repair proteins A key mechanistic model is selective nuclear import failure: mutant ALADIN reduces nuclear import of DNA ligase I and aprataxin, proteins needed for repair of DNA single-strand breaks, linking AAAS dysfunction to genome maintenance defects (braun2026pathologiesatthe pages 10-12, cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14) Mechanistic review of primary studies Cehic et al., Sep 2024, Front Endocrinol, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 1-3); Ruiz-Babot et al., Nov 2023, https://doi.org/10.1016/j.crmeth.2023.100627 (ruizbabot2023generationofglucocorticoidproducing pages 12-14)
Cargoes/processes affected: ferritin heavy chain ALADIN dysfunction also impairs nuclear import of ferritin heavy chain (FTH1), a protective factor against nuclear oxidative damage; this supports the widely cited model that oxidative stress susceptibility is central to AAAS pathology (smits2024biallelicndc1variants pages 8-10, braun2026pathologiesatthe pages 10-12, cehic2024veryearlyand pages 8-9, smits2024biallelicndc1variants pages 11-12, ruizbabot2023generationofglucocorticoidproducing pages 12-14) Cell/mechanistic assay summarized by recent review Smits et al., Oct 2024, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10, smits2024biallelicndc1variants pages 11-12); Cehic et al., Sep 2024, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 8-9)
Core molecular function Best-supported current interpretation: ALADIN is a scaffold/selective transport regulator at the NPC, not an enzyme or transporter with a defined small-molecule substrate. Its primary role is to enable proper nucleocytoplasmic trafficking of selected protein cargos, thereby supporting DNA repair, redox homeostasis, and tissue-specific functions in adrenal and neural cells (braun2026pathologiesatthe pages 9-10, cehic2024veryearlyand pages 1-3, ruizbabot2023generationofglucocorticoidproducing pages 12-14) Review synthesis + disease modeling Cehic et al., Sep 2024, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 1-3); Ruiz-Babot et al., Nov 2023, https://doi.org/10.1016/j.crmeth.2023.100627 (ruizbabot2023generationofglucocorticoidproducing pages 12-14)
Redox / oxidative stress role Multiple recent sources summarize increased ROS/oxidative stress in AAAS-deficient contexts; ALADIN loss alters oxidative-stress responses in fibroblasts/adrenal cells, and antioxidant response has been proposed as a therapeutic angle in isolated reports (smits2024biallelicndc1variants pages 8-10, cehic2024veryearlyand pages 8-9, cehic2024veryearlyand pages 5-6, cehic2024veryearlyand pages 4-5) Case-review synthesis; cell assay summaries Cehic et al., Sep 2024, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 8-9, cehic2024veryearlyand pages 5-6, cehic2024veryearlyand pages 4-5); Smits et al., Oct 2024, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10)
Steroidogenesis / adrenal pathway AAAS dysfunction is linked to adrenal steroidogenic failure. In patient adrenal tissue, SCARB1 transcript is reduced, MC2R is strongly reduced, and phospho-PKA shows decreased nuclear and increased cytosolic localization, consistent with impaired cAMP/PKA-dependent nuclear signaling and ACTH resistance (bitetto2023scarb1downregulationin pages 4-6, bitetto2023scarb1downregulationin pages 6-8, bitetto2023scarb1downregulationin pages 1-2) Patient tissue study Bitetto et al., Jun 2023, Orphanet J Rare Dis, https://doi.org/10.1186/s13023-023-02763-w (bitetto2023scarb1downregulationin pages 4-6, bitetto2023scarb1downregulationin pages 6-8, bitetto2023scarb1downregulationin pages 1-2)
Human cell disease modeling CRISPR-engineered AAAS-null iPSC-derived steroidogenic cells recapitulate adrenal insufficiency features, showing significantly lower cortisol, cortisone, corticosterone, and aldosterone secretion than controls; this is a direct 2023 implementation for functional modeling of AAAS-associated disease (ruizbabot2023generationofglucocorticoidproducing pages 12-14, ruizbabot2023generationofglucocorticoidproducing pages 3-4, ruizbabot2023generationofglucocorticoidproducing pages 1-3) iPSC disease model Ruiz-Babot et al., Nov 2023, https://doi.org/10.1016/j.crmeth.2023.100627 (ruizbabot2023generationofglucocorticoidproducing pages 12-14, ruizbabot2023generationofglucocorticoidproducing pages 3-4, ruizbabot2023generationofglucocorticoidproducing pages 1-3)
Disease association Biallelic AAAS variants cause triple A (Allgrove) syndrome, classically comprising alacrima, achalasia, and adrenal insufficiency, often with neurologic/autonomic involvement; ALADIN mislocalization from the NPC is a common pathogenic theme (cehic2024veryearlyand pages 1-3, hasenmajer2023rareformsof pages 9-10) Review Hasenmajer et al., Feb 2023, https://doi.org/10.1007/s11154-023-09784-7 (hasenmajer2023rareformsof pages 9-10); Cehic et al., Sep 2024, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 1-3)
Key 2023–2024 clinical statistics Recent reviews/case analyses report: complete triad ~70%; alacrima >90% or 90–100%; achalasia 75–85%; primary adrenal insufficiency almost 85%; neurologic involvement ~60% to two-thirds; AAAS variants in ~90% of patients in one 2023 review; disease prevalence cited as about 1 in 1,000,000 in review literature (cehic2024veryearlyand pages 1-3, cehic2024veryearlyand pages 4-5, hasenmajer2023rareformsof pages 9-10, hasenmajer2023rareformsof pages 8-9, braun2026pathologiesatthe pages 9-10) Review; case-review synthesis Hasenmajer et al., Feb 2023, https://doi.org/10.1007/s11154-023-09784-7 (hasenmajer2023rareformsof pages 9-10, hasenmajer2023rareformsof pages 8-9); Cehic et al., Sep 2024, https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 1-3, cehic2024veryearlyand pages 4-5)
Notable genotype/phenotype data In a 2024 genotype-focused summary, the p.Ser263Pro AAAS variant showed neurologic manifestations in 33/34 (97.1%) carriers versus 133/172 (77.3%) in other genotypes (p = 0.006); possible Slavic founder effect noted (25/36, 69.4%) (juscinska2026neurologicalmanifestationsof pages 1-2) Cohort/genotype-phenotype analysis Juścińska et al., Jan 2026 reporting aggregate cohort data, https://doi.org/10.1007/s10048-025-00870-3 (juscinska2026neurologicalmanifestationsof pages 1-2)
Recent clinical implementation Current real-world use is mainly molecular diagnosis and mechanistic stratification of rare disease: recent Sudanese series identified 6 AAAS mutations in 20 families/31 patients, including novel alleles, emphasizing early genetic diagnosis to prevent adrenal crises; NDC1 analysis expands differential diagnosis to triple A-like syndromes when AAAS is negative (smits2024biallelicndc1variants pages 8-10) Case series / genetic diagnostics Smits et al., Oct 2024, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10)
Visual/mechanistic support from recent figure A recent figure shows reduced ALADIN nuclear-envelope staining in NDC1-variant fibroblasts and lower post-mitotic NPC density in patient cells, visually supporting the ALADIN-at-NPC recruitment model (smits2024biallelicndc1variants media 042ddde5) Figure-based cell assay Smits et al., Oct 2024, Figure 4 context, https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants media 042ddde5)

Table: This table condenses the most relevant verified facts about human AAAS/ALADIN, including identity, NPC localization, interaction partners, mechanisms, disease links, and recent 2023–2024 studies. It is designed as a quick-reference artifact for functional annotation and evidence-weighted interpretation.

References (URLs and publication dates)

  • Bitetto G. et al. Jun 2023. Orphanet Journal of Rare Diseases. “SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome.” https://doi.org/10.1186/s13023-023-02763-w (bitetto2023scarb1downregulationin pages 1-2)
  • Hasenmajer V. et al. Feb 2023. Reviews in Endocrine & Metabolic Disorders. “Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia.” https://doi.org/10.1007/s11154-023-09784-7 (hasenmajer2023rareformsof pages 9-10)
  • Ruiz-Babot G. et al. Nov 2023. Cell Reports Methods. “Generation of glucocorticoid-producing cells derived from human pluripotent stem cells.” https://doi.org/10.1016/j.crmeth.2023.100627 (ruizbabot2023generationofglucocorticoidproducing pages 1-3)
  • Cehic M. et al. Sep 2024. Frontiers in Endocrinology. “Very early and severe presentation of Triple A syndrome – case report and review of the literature.” https://doi.org/10.3389/fendo.2024.1431383 (cehic2024veryearlyand pages 1-3)
  • Smits D.J. et al. Oct 2024. Human Genetics and Genomics Advances. “Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome.” https://doi.org/10.1016/j.xhgg.2024.100327 (smits2024biallelicndc1variants pages 8-10)

Notes on limitations of this synthesis

Some extracted excerpts describe statistical significance or “significant” changes without providing full numeric effect sizes; therefore, this report reports quantitative values only where explicitly present in the retrieved text (e.g., NPC density metrics) and otherwise reports qualitative directionality with clear attribution. (bitetto2023scarb1downregulationin pages 6-8, ruizbabot2023generationofglucocorticoidproducing pages 12-14)

References

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  15. (ruizbabot2023generationofglucocorticoidproducing pages 21-23): Gerard Ruiz-Babot, Ariane Eceiza, Fernando Abollo-Jiménez, Maria Malyukov, Diana L. Carlone, Kleiton Borges, Alexandra Rodrigues Da Costa, Shamma Qarin, Takuya Matsumoto, Ryuji Morizane, William C. Skarnes, Barbara Ludwig, Paul J. Chapple, Leonardo Guasti, Helen L. Storr, Stefan R. Bornstein, and David T. Breault. Generation of glucocorticoid-producing cells derived from human pluripotent stem cells. Cell Reports Methods, 3:100627, Nov 2023. URL: https://doi.org/10.1016/j.crmeth.2023.100627, doi:10.1016/j.crmeth.2023.100627. This article has 20 citations.

  16. (cehic2024veryearlyand pages 5-6): Maja Cehic, Katarina Mitrovic, Rade Vukovic, Tatjana Milenkovic, Gordana Kovacevic, Sladjana Todorovic, Sanja Panic Zaric, Dimitrije Cvetkovic, Aleksandra Paripovic, Angela Huebner, Katrin Koehler, and Friederike Quitter. Very early and severe presentation of triple a syndrome – case report and review of the literature. Frontiers in Endocrinology, Sep 2024. URL: https://doi.org/10.3389/fendo.2024.1431383, doi:10.3389/fendo.2024.1431383. This article has 11 citations.

  17. (ruizbabot2023generationofglucocorticoidproducing pages 15-16): Gerard Ruiz-Babot, Ariane Eceiza, Fernando Abollo-Jiménez, Maria Malyukov, Diana L. Carlone, Kleiton Borges, Alexandra Rodrigues Da Costa, Shamma Qarin, Takuya Matsumoto, Ryuji Morizane, William C. Skarnes, Barbara Ludwig, Paul J. Chapple, Leonardo Guasti, Helen L. Storr, Stefan R. Bornstein, and David T. Breault. Generation of glucocorticoid-producing cells derived from human pluripotent stem cells. Cell Reports Methods, 3:100627, Nov 2023. URL: https://doi.org/10.1016/j.crmeth.2023.100627, doi:10.1016/j.crmeth.2023.100627. This article has 20 citations.

  18. (cehic2024veryearlyand pages 4-5): Maja Cehic, Katarina Mitrovic, Rade Vukovic, Tatjana Milenkovic, Gordana Kovacevic, Sladjana Todorovic, Sanja Panic Zaric, Dimitrije Cvetkovic, Aleksandra Paripovic, Angela Huebner, Katrin Koehler, and Friederike Quitter. Very early and severe presentation of triple a syndrome – case report and review of the literature. Frontiers in Endocrinology, Sep 2024. URL: https://doi.org/10.3389/fendo.2024.1431383, doi:10.3389/fendo.2024.1431383. This article has 11 citations.

  19. (hasenmajer2023rareformsof pages 8-9): Valeria Hasenmajer, Rosario Ferrigno, Marianna Minnetti, Bianca Pellegrini, Andrea M. Isidori, Andrea Lenzi, Mariacarolina Salerno, Marco Cappa, Li Chan, Maria Cristina De Martino, and Martin O. Savage. Rare forms of genetic paediatric adrenal insufficiency: excluding congenital adrenal hyperplasia. Reviews in Endocrine & Metabolic Disorders, 24:345-363, Feb 2023. URL: https://doi.org/10.1007/s11154-023-09784-7, doi:10.1007/s11154-023-09784-7. This article has 22 citations and is from a peer-reviewed journal.

  20. (braun2026pathologiesatthe pages 23-24): Daniela A. Braun, Ramona Jühlen, Vanessa Krausel, and Wolfram Antonin. Pathologies at the gateway: exploring the link between nucleoporins and inherited diseases. Cellular and Molecular Life Sciences, Apr 2026. URL: https://doi.org/10.1007/s00018-026-06220-2, doi:10.1007/s00018-026-06220-2. This article has 0 citations and is from a domain leading peer-reviewed journal.

  21. (braun2026pathologiesatthe pages 9-10): Daniela A. Braun, Ramona Jühlen, Vanessa Krausel, and Wolfram Antonin. Pathologies at the gateway: exploring the link between nucleoporins and inherited diseases. Cellular and Molecular Life Sciences, Apr 2026. URL: https://doi.org/10.1007/s00018-026-06220-2, doi:10.1007/s00018-026-06220-2. This article has 0 citations and is from a domain leading peer-reviewed journal.

  22. (juscinska2026neurologicalmanifestationsof pages 1-2): Ewa Juścińska, Karolina Gadzalska, Paulina Jakiel, Monika Gorządek, Michał Pietrusiński, Tomasz Płoszaj, Sebastian Skoczylas, Klaudia Starosz, Maciej Borowiec, Agata Pastorczak, and Agnieszka Zmysłowska. Neurological manifestations of allgrove syndrome in patients carrying a potentially founder p.ser263pro variant in the aaas gene. Neurogenetics, Jan 2026. URL: https://doi.org/10.1007/s10048-025-00870-3, doi:10.1007/s10048-025-00870-3. This article has 2 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. ruizbabot2023generationofglucocorticoidproducing pages 12-14
  2. cehic2024veryearlyand pages 5-6
  3. hasenmajer2023rareformsof pages 9-10
  4. braun2026pathologiesatthe pages 23-24
  5. cehic2024veryearlyand pages 1-3
  6. cehic2024veryearlyand pages 8-9
  7. juscinska2026neurologicalmanifestationsof pages 1-2
  8. ruizbabot2023generationofglucocorticoidproducing pages 1-3
  9. ruizbabot2023generationofglucocorticoidproducing pages 3-4
  10. braun2026pathologiesatthe pages 10-12
  11. ruizbabot2023generationofglucocorticoidproducing pages 21-23
  12. ruizbabot2023generationofglucocorticoidproducing pages 15-16
  13. cehic2024veryearlyand pages 4-5
  14. hasenmajer2023rareformsof pages 8-9
  15. braun2026pathologiesatthe pages 9-10
  16. https://doi.org/10.1016/j.xhgg.2024.100327
  17. https://doi.org/10.1186/s13023-023-02763-w
  18. https://doi.org/10.1016/j.crmeth.2023.100627
  19. https://doi.org/10.3389/fendo.2024.1431383
  20. https://doi.org/10.1007/s11154-023-09784-7
  21. https://doi.org/10.1007/s00018-026-06220-2
  22. https://doi.org/10.1007/s10048-025-00870-3
  23. https://doi.org/10.1016/j.crmeth.2023.100627,
  24. https://doi.org/10.1007/s11154-023-09784-7,
  25. https://doi.org/10.3389/fendo.2024.1431383,
  26. https://doi.org/10.1016/j.xhgg.2024.100327,
  27. https://doi.org/10.1007/s00018-026-06220-2,
  28. https://doi.org/10.1186/s13023-023-02763-w,
  29. https://doi.org/10.1007/s10048-025-00870-3,

📚 Additional Documentation

Notes

(AAAS-notes.md)

AAAS review notes

  • AAAS encodes ALADIN, a WD-repeat nucleoporin mutated in triple-A syndrome. The original disease-gene reports describe ALADIN as a WD-repeat regulatory protein and link expression to neuroendocrine, gastrointestinal, and cerebral structures affected in disease [PMID:11062474 "The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins" ; PMID:11159947 "RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures"].
  • The core GO context is nuclear pore/nuclear envelope and regulation/support of nucleocytoplasmic transport. Disease-associated ALADIN variants fail to target NPCs, but patient cells did not show gross nuclear-envelope or NPC morphology defects, supporting a functional transport/regulatory interpretation rather than an NPC-structure-loss annotation [PMID:12730363 "A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs" ; PMID:12730363 "defects in NPC function, rather than structure, give rise to triple A syndrome"].
  • NDC1 anchoring is a strong ALADIN-specific nuclear-envelope localization source: NDC1 depletion mislocalizes ALADIN, ALADIN depletion affects NDC1 at NPCs, and FRET supports direct association PMID:19782045.
  • The AURKA/spindle paper supports a second well-evidenced AAAS function in mitosis. I kept mitotic spindle/spindle pole and mitotic spindle assembly, while treating microtubule bundle formation as non-core because it is a less direct description of the phenotype than spindle assembly and Aurora A spatial regulation [PMID:26246606 "Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules" ; PMID:26246606 "slows spindle assembly and chromosome alignment"].
  • The PGRMC2 interaction is documented but not retained as GO:0005515 protein binding. It is useful biological context for adrenal/steroidogenesis hypotheses, but the generic binding term does not describe AAAS molecular function PMID:27754849.
  • The Proteostasis PN projection lists AAAS under Nuclear proteostasis | Protein transport | Nuclear pore complex and proposes GO:0015031 protein transport as new to GOA. I did not add this as a NEW annotation because existing GOA already has the more informative GO:0006913 nucleocytoplasmic transport and GO:0046822 regulation of nucleocytoplasmic transport, and the PN candidate is a broad class-level projection rather than gene-level evidence for generic protein transport [file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv "AAAS GO:0015031 protein transport"].
  • Falcon deep research was run for AAAS and produced AAAS-deep-research-falcon.md plus an artifact table. The wrapper returned nonzero after reporting a Falcon timeout and failed fallback, but the Falcon report itself contains usable synthesis consistent with the primary-literature review: ALADIN is an NPC/nuclear-envelope scaffold with NDC1-dependent targeting and selective transport/regulatory effects rather than enzymatic activity [file:human/AAAS/AAAS-deep-research-falcon.md "Best-supported current interpretation: ALADIN is a scaffold/selective transport regulator at the NPC, not an enzyme or transporter with a defined small-molecule substrate."].

Pn Notes

(AAAS-pn-notes.md)

AAAS PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9NRG9
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-03 (PR 1325)
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: AAAS encodes ALADIN, a WD-repeat scaffold nucleoporin of the nuclear pore complex. ALADIN is anchored at the nuclear envelope through NDC1 and contributes to normal NPC-associated nucleocytoplasmic transport, especially in tissues affected by triple-A syndrome such as adrenal, gastrointestinal, and neural systems. In mitosis, ALADIN also localizes to spindle structures and helps spatially regulate inactive Aurora A and downstream spindle factors, supporting robust spindle formation and chromosome alignment.
  • Existing/core annotation action counts: ACCEPT: 45; KEEP_AS_NON_CORE: 2; MARK_AS_OVER_ANNOTATED: 2; REMOVE: 2

PN Consistency Summary

  • Consistency: Consistent. Deep research (NDC1-anchored NPC scaffold / selective transport regulator), the review (ALADIN nucleoporin; nuclear pore + nucleocytoplasmic transport; plus a mitotic spindle/Aurora-A side role), and the PN annotation all agree on the NPC/transport identity. The review explicitly engages the PN projection and declines GO:0015031 as too broad, retaining the more specific GO:0006913 nucleocytoplasmic transport instead. This is a deliberate, documented divergence, not a contradiction.
  • PN story / NEW pressure: PN's "protein transport" story is already captured at a more informative level by existing GO:0006913 nucleocytoplasmic transport (IBA/NAS) and GO:0005643 nuclear pore (multiple evidence codes). GO:0015031 is a real term but is a broad parent of GO:0006913. Conclusion: already captured (more specifically); PN's class-level projection over-reaches toward a broad parent.
  • Evidence alignment: PN dossier lists no reference titles. Review cites ALADIN-specific PMIDs (12730363, 19782045 NDC1 anchoring, 27016207, 24315095) plus the spindle paper (26246606) — consistent with the NPC node; the spindle/Aurora-A biology is outside the PN nuclear-transport frame (not in PN, legitimately reviewer-added). No citation conflict.
  • Verdict: Consistent; PN protein-transport projection correctly rejected as broader (review keeps narrower GO:0006913). No edits warranted.

Full Consistency Review

  • UniProt: Q9NRG9 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
  • PN placement: Nuclear proteostasis|Protein transport|Nuclear pore complex ; PN-node mapping: group Nuclear pore complex=mapped→GO:0005643 nuclear pore (already_in_goa_exact); class Protein transport=mapped→GO:0015031 protein transport (new_to_goa); branch Nuclear proteostasis=no_mapping.
  • Consistency: Consistent. Deep research (NDC1-anchored NPC scaffold / selective transport regulator), the review (ALADIN nucleoporin; nuclear pore + nucleocytoplasmic transport; plus a mitotic spindle/Aurora-A side role), and the PN annotation all agree on the NPC/transport identity. The review explicitly engages the PN projection and declines GO:0015031 as too broad, retaining the more specific GO:0006913 nucleocytoplasmic transport instead. This is a deliberate, documented divergence, not a contradiction.
  • PN story / NEW pressure: PN's "protein transport" story is already captured at a more informative level by existing GO:0006913 nucleocytoplasmic transport (IBA/NAS) and GO:0005643 nuclear pore (multiple evidence codes). GO:0015031 is a real term but is a broad parent of GO:0006913. Conclusion: already captured (more specifically); PN's class-level projection over-reaches toward a broad parent.
  • Mapping strategy: Matches the TOMM20/HSPA8/RAB7A precedent — the PN-projected GO:0015031 is broader than what the review already holds and is correctly NOT added. Group-node GO:0005643 is right (already in GOA). Class-node Protein transport→GO:0015031 should be treated as context-only / non-propagating for AAAS, since gene-specific evidence supports the narrower nucleocytoplasmic-transport term.
  • Evidence alignment: PN dossier lists no reference titles. Review cites ALADIN-specific PMIDs (12730363, 19782045 NDC1 anchoring, 27016207, 24315095) plus the spindle paper (26246606) — consistent with the NPC node; the spindle/Aurora-A biology is outside the PN nuclear-transport frame (not in PN, legitimately reviewer-added). No citation conflict.
  • Verdict: Consistent; PN protein-transport projection correctly rejected as broader (review keeps narrower GO:0006913). No edits warranted.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-03
  • review_yaml: genes/human/AAAS/AAAS-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Nuclear proteostasis | Protein transport | Nuclear pore complex

  • UniProt: Q9NRG9
  • In branches: NU
  • PN-node mapping records (path + ancestors):
    • [group] Nuclear proteostasis|Protein transport|Nuclear pore complex
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0005643 nuclear pore]
      rationale: This PN group denotes core components of the nuclear pore complex. The closest current GO target in the local ontology cache is the cellular-component term nuclear pore.
    • [class] Nuclear proteostasis|Protein transport
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
      rationale: The PN nuclear Protein transport class covers the machinery and routes that move proteins across the nuclear envelope. GO protein transport is the correct propagation target, although the PN class is specialized to the nuclear compartment.
    • [branch] Nuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

  • GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Nuclear proteostasis|Protein transport
  • GO:0005643 nuclear pore | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Nuclear proteostasis|Protein transport|Nuclear pore complex

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q9NRG9
gene_symbol: AAAS
product_type: PROTEIN
status: COMPLETE
description: 'AAAS encodes ALADIN, a WD-repeat scaffold nucleoporin of the nuclear pore complex. ALADIN is anchored at the nuclear envelope through NDC1 and contributes to normal NPC-associated nucleocytoplasmic transport, especially in tissues affected by triple-A syndrome such as adrenal, gastrointestinal, and neural systems. In mitosis, ALADIN also localizes to spindle structures and helps spatially regulate inactive Aurora A and downstream spindle factors, supporting robust spindle formation and chromosome alignment.'
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
alternative_products:
- name: 1 (AAAS-v1)
  id: Q9NRG9-1
- name: 2 (AAAS-v2)
  id: Q9NRG9-2
  sequence_note: VSP_043014
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:24315095
  title: Integrated structural analysis of the human nuclear pore complex scaffold.
  full_text_unavailable: true
  findings:
  - statement: The human NPC scaffold is a multi-nucleoporin assembly mediating nucleocytoplasmic exchange.
    supporting_text: The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules.
    full_text_unavailable: true
- id: PMID:27016207
  title: The Structure Inventory of the Nuclear Pore Complex.
  findings:
  - statement: NPCs are the principal gateway for nuclear-cytoplasmic exchange.
    supporting_text: The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.
  - statement: NPCs are built from about 30 nucleoporins and positioned in nuclear-envelope openings.
    supporting_text: Analyzing the protein composition of NPCs from various eukaryotic origin reveals that they all share a set of ~30 nucleoporins (Nups).
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:28811369
  title: Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.
  full_text_unavailable: true
  findings:
  - statement: TMEM18 interacts with nuclear pore complex components, but this does not establish a specific AAAS molecular function beyond a generic interaction.
    supporting_text: We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex.
    full_text_unavailable: true
- id: PMID:27754849
  title: Identification of a novel putative interaction partner of the nucleoporin ALADIN.
  findings:
  - statement: PGRMC2 co-immunoprecipitates with ALADIN in adrenal cell models.
    supporting_text: In an attempt to identify new interaction partners of ALADIN, co-IP analyses showed that PGRMC2 precipitated with ALADIN.
  - statement: ALADIN and PGRMC2 are associated near the nuclear envelope/perinuclear ER.
    supporting_text: Taken together, our results in immunofluorescence microscopy using different ALADIN and PGRMC2 adrenal cell expression systems provide a basis for future research of how ALADIN and PGRMC2 possibly associate in a complex close to the nuclear envelope, and what the effects on steroidogenesis of this association would be.
- id: PMID:26246606
  title: The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation.
  findings:
  - statement: ALADIN regulates Aurora A localization during mitotic spindle formation.
    supporting_text: In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A.
  - statement: ALADIN loss slows spindle assembly and chromosome alignment.
    supporting_text: Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
  - statement: ALADIN interacts with inactive Aurora A and is recruited to spindle poles after Aurora A inhibition.
    supporting_text: ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
- id: PMID:12730363
  title: The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.
  full_text_unavailable: true
  findings:
  - statement: ALADIN localizes to nuclear pore complexes.
    supporting_text: ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
    full_text_unavailable: true
  - statement: Patient mutations disrupt NPC targeting while leaving gross NPC structure intact.
    supporting_text: A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm.
    full_text_unavailable: true
  - statement: The authors proposed a regulatory role in nucleocytoplasmic transport.
    supporting_text: We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
    full_text_unavailable: true
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  full_text_unavailable: true
  findings:
  - statement: AAAS was identified in a high-throughput membrane proteomics data set; the paper cautions that many identified proteins may only be transiently membrane-associated.
    supporting_text: The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
    full_text_unavailable: true
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  full_text_unavailable: true
  findings:
  - statement: AAAS was detected in an isolated sperm nucleus proteomics data set.
    supporting_text: With this approach, 403 different proteins have been identified from the isolated sperm nuclei.
    full_text_unavailable: true
- id: Reactome:R-HSA-1176059
  title: Translocation of Influenza A virus nonstructural protein 1 (NS1A) into the nucleus
  findings: []
- id: Reactome:R-HSA-165043
  title: Rev multimer-bound HIV mRNA:Crm1:Ran:GTP complex associates with the NPC
  findings: []
- id: Reactome:R-HSA-165047
  title: Translocation of nuclear RNA transport complex to cytoplasm
  findings: []
- id: Reactome:R-HSA-170796
  title: NPC transports GCK1:GCKR from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-180622
  title: Vpr binds nucleoporins
  findings: []
- id: Reactome:R-HSA-192627
  title: Viral mRNA Export
  findings: []
- id: Reactome:R-HSA-192925
  title: Export of Spliced Viral mRNA
  findings: []
- id: Reactome:R-HSA-2990880
  title: NEK6/NEK7 phosphorylates NUP98
  findings: []
- id: Reactome:R-HSA-2990882
  title: CDK1 phosphorylates NUP98
  findings: []
- id: Reactome:R-HSA-3000348
  title: RANBP2 SUMOylates SP100 with SUMO2
  findings: []
- id: Reactome:R-HSA-3000399
  title: RANBP2 SUMOylates SP100 with SUMO1
  findings: []
- id: Reactome:R-HSA-3000411
  title: RANBP2 SUMOylates PML with SUMO2
  findings: []
- id: Reactome:R-HSA-4551649
  title: RANBP2 SUMOylates RANBP2 with SUMO1
  findings: []
- id: Reactome:R-HSA-4551679
  title: RANBP2 SUMOylates RANBP2 with SUMO2
  findings: []
- id: Reactome:R-HSA-4570493
  title: RANBP2 (NUP358) SUMOylates HNRNPC with SUMO1
  findings: []
- id: Reactome:R-HSA-4615872
  title: RANBP2 SUMOylates HDAC4 with SUMO1
  findings: []
- id: Reactome:R-HSA-4615987
  title: RANBP2 SUMOylates HDAC4 with SUMO2,3
  findings: []
- id: Reactome:R-HSA-4655355
  title: RANBP2 SUMOylates CDCA8 (Borealin) and PIAS3 SUMOylates AURKB (Aurora-B)
  findings: []
- id: Reactome:R-HSA-5228508
  title: RANBP2 SUMOylates PML with SUMO1
  findings: []
- id: Reactome:R-HSA-5228523
  title: RANBP2 SUMOylates MDM2 with SUMO1
  findings: []
- id: Reactome:R-HSA-5252041
  title: NPC transports Hikeshi:HSP70s:ATP from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-5661474
  title: Defective NPC does not transport GCK1:GKRP from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-6783483
  title: tRNA:XPOT:RAN:GTP translocates from the nucleus to the cytosol
  findings: []
- id: Reactome:R-HSA-75096
  title: Docking of the TAP:EJC Complex with the NPC
  findings: []
- id: Reactome:R-HSA-75097
  title: Transport of the export-competent mRNP complex through the NPC
  findings: []
- id: Reactome:R-HSA-75098
  title: mRNP complex dissociates from cytosolic face of NPC
  findings: []
- id: Reactome:R-HSA-9614367
  title: HCMV Nuclear Pore Docking
  findings: []
- id: Reactome:R-HSA-9614369
  title: Transport of HCMV DNA Into the Nucleus
  findings: []
- id: Reactome:R-HSA-9708889
  title: SARS-CoV-2 6 binds NUP98:RAE1 within NPC
  findings: []
- id: PMID:11062474
  title: Mutant WD-repeat protein in triple-A syndrome.
  full_text_unavailable: true
  findings:
  - statement: AAAS encodes ALADIN, a WD-repeat protein mutated in triple-A syndrome.
    supporting_text: The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome.
    full_text_unavailable: true
  - statement: Expression in affected neuroendocrine and cerebral structures supports developmental and neurological relevance.
    supporting_text: The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
    full_text_unavailable: true
- id: PMID:11159947
  title: Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.
  full_text_unavailable: true
  findings:
  - statement: Loss-of-function AAAS mutations cause triple-A syndrome.
    supporting_text: In nine triple A syndrome patients eight different homozygous and compound heterozygous mutations were found in this gene, most of them leading to a truncated protein suggesting loss of function.
    full_text_unavailable: true
  - statement: AAAS is expressed in neuroendocrine and gastrointestinal structures affected in disease.
    supporting_text: RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple A syndrome, supporting the hypothesis that mutations in this triple A syndrome gene (AAAS) are responsible for the disease.
    full_text_unavailable: true
- id: PMID:16022285
  title: Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS.
  full_text_unavailable: true
  findings:
  - statement: AAAS has a shorter splice variant that remains broadly expressed.
    supporting_text: RT-PCR analysis in our work revealed that AAAS-v2 and AAAS-v1 were ubiquitously detected in human multiple tissue cDNA (MTC) panels (CLONTECH).
    full_text_unavailable: true
- id: PMID:19782045
  title: The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope.
  full_text_unavailable: true
  findings:
  - statement: ALADIN is anchored in the NPC through NDC1.
    supporting_text: We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
    full_text_unavailable: true
  - statement: Loss of ALADIN integration into the NPC is disease-relevant.
    supporting_text: The loss of integration of ALADIN in the NPC is a main pathogenetic aspect for the development of the triple A syndrome and suggests that the interaction between ALADIN and NDC1 may be involved in the pathogenesis of the disease.
    full_text_unavailable: true
- id: file:human/AAAS/AAAS-uniprot.txt
  title: UniProtKB Q9NRG9 AAAS/ALADIN record
  findings:
  - statement: UniProt summarizes ALADIN as an NPC protein with roles in AURKA/NUMA1 localization and spindle formation.
    supporting_text: Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment
  - statement: UniProt records the nuclear pore complex, spindle pole, and nuclear envelope locations.
    supporting_text: Nucleus, nuclear pore complex
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
  title: Proteostasis PN projected candidate additions for AAAS
  findings:
  - statement: PN projection suggests GO:0015031 protein transport from Nuclear proteostasis | Protein transport, but this is a broad class-level projection and is not added as a new AAAS annotation in this conservative review.
    supporting_text: "AAAS\t\tGO:0015031\tprotein transport\tnew_to_goa\tok_for_propagation_to_go\tnuclear_proteostasis.yaml\tNuclear proteostasis|Protein transport\tNuclear proteostasis|Protein transport|Nuclear pore complex"
- id: file:human/AAAS/AAAS-deep-research-falcon.md
  title: Falcon deep research report for human AAAS
  findings:
  - statement: Falcon deep research summarizes AAAS/ALADIN as an NPC/nuclear-envelope scaffold whose localization is NDC1-dependent.
    supporting_text: ALADIN localizes to the **NPC/nuclear envelope**; proper NE/NPC targeting is **NDC1-dependent**.
  - statement: Falcon deep research treats ALADIN as a scaffold/selective transport regulator rather than an enzyme or small-molecule transporter.
    supporting_text: 'Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate.'
existing_annotations:
- term:
    id: GO:0005643
    label: nuclear pore
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
    action: ACCEPT
    reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - &id001
      reference_id: PMID:12730363
      supporting_text: ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
      reference_section_type: ABSTRACT
    - &id002
      reference_id: PMID:19782045
      supporting_text: We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006913
    label: nucleocytoplasmic transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
    action: ACCEPT
    reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - &id003
      reference_id: PMID:12730363
      supporting_text: We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues.
      reference_section_type: ABSTRACT
    - &id004
      reference_id: PMID:27016207
      supporting_text: The nuclear pore complex (NPC) is the principal gateway for molecular exchange between nucleus and cytoplasm across the nuclear envelope.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ALADIN localizes to mitotic spindle structures, including the spindle pole, in the AURKA/spindle study.
    action: ACCEPT
    reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
    supported_by:
    - &id005
      reference_id: PMID:26246606
      supporting_text: Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment.
      reference_section_type: ABSTRACT
    - &id006
      reference_id: PMID:26246606
      supporting_text: ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear envelope/nuclear membrane localization is consistent with ALADIN being an NPC nucleoporin anchored through NDC1.
    action: ACCEPT
    reason: This cellular component is well supported by ALADIN-specific localization and anchoring evidence. For the HPA-derived nuclear membrane row, the term is less specific than nuclear pore but still consistent with the NPC location at the nuclear envelope.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005643
    label: nuclear pore
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: part_of
  review:
    summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
    action: ACCEPT
    reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id001
    - *id002
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: IDA
  original_reference_id: PMID:24315095
  qualifier: located_in
  review:
    summary: The original structural NPC-scaffold source has only abstract text available locally, but independent ALADIN-specific evidence supports nuclear-envelope/NPC localization.
    action: ACCEPT
    reason: Retain the nuclear envelope annotation because ALADIN is directly shown to be anchored in the nuclear envelope via NDC1. The unavailable original full text limits direct assessment of the 2013 structural study details, so the review also relies on ALADIN-specific localization evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:24315095
      supporting_text: The nuclear pore complex (NPC) is a fundamental component of all eukaryotic cells that facilitates nucleocytoplasmic exchange of macromolecules.
      reference_section_type: ABSTRACT
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005643
    label: nuclear pore
  evidence_type: NAS
  original_reference_id: PMID:24315095
  qualifier: part_of
  review:
    summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
    action: ACCEPT
    reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id001
    - *id002
- term:
    id: GO:0006913
    label: nucleocytoplasmic transport
  evidence_type: NAS
  original_reference_id: PMID:27016207
  qualifier: involved_in
  review:
    summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
    action: ACCEPT
    reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id003
    - *id004
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: The HPA-derived nucleoplasm signal is plausible for an NPC-associated protein but is less specific than nuclear pore/nuclear envelope localization.
    action: KEEP_AS_NON_CORE
    reason: AAAS should primarily be represented as a nuclear pore/nuclear envelope component. Nucleoplasm localization may reflect immunofluorescence signal or cell-state context and is not the best descriptor of the core site of action.
    supported_by:
    - reference_id: PMID:12730363
      supporting_text: ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Nuclear envelope/nuclear membrane localization is consistent with ALADIN being an NPC nucleoporin anchored through NDC1.
    action: ACCEPT
    reason: This cellular component is well supported by ALADIN-specific localization and anchoring evidence. For the HPA-derived nuclear membrane row, the term is less specific than nuclear pore but still consistent with the NPC location at the nuclear envelope.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28811369
  qualifier: enables
  review:
    summary: This protein binding row comes from a TMEM18 study that reports interaction with NPC components. It does not define a specific AAAS molecular function.
    action: REMOVE
    reason: GO:0005515 protein binding is too generic for curation and the source is primarily about TMEM18 biology. The finding may identify AAAS as an NPC component/interactor, but that context is already captured by nuclear pore and nucleocytoplasmic transport annotations.
    supported_by:
    - reference_id: PMID:28811369
      supporting_text: We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27754849
  qualifier: enables
  review:
    summary: The PGRMC2 interaction with ALADIN is experimentally supported, but protein binding is uninformative as a GO molecular-function annotation.
    action: REMOVE
    reason: The interaction should be retained as biological evidence in the notes/reference findings, not as the generic GO:0005515 term. No more specific AAAS molecular-function term is supported strongly enough from this interaction alone.
    supported_by:
    - reference_id: PMID:27754849
      supporting_text: In an attempt to identify new interaction partners of ALADIN, co-IP analyses showed that PGRMC2 precipitated with ALADIN.
      reference_section_type: DISCUSSION
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: IDA
  original_reference_id: PMID:27754849
  qualifier: located_in
  review:
    summary: ALADIN is observed at the nuclear envelope/perinuclear region in adrenal-cell interaction experiments with PGRMC2.
    action: ACCEPT
    reason: This is consistent with the core NPC/nuclear-envelope localization of AAAS. The PGRMC2 paper supports nuclear-envelope localization and an interaction context, but it should not be inflated into a specific transport or steroidogenesis GO process for AAAS.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:27754849
      supporting_text: We detected that PGRMC2 co-localises with ALADIN and with different FG-repeat NUPs [stained with anti-NPC proteins (mAb414)] to the nuclear envelope and the perinuclear ER.
      reference_section_type: RESULTS
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0000922
    label: spindle pole
  evidence_type: IDA
  original_reference_id: PMID:26246606
  qualifier: located_in
  review:
    summary: ALADIN localizes to mitotic spindle structures, including the spindle pole, in the AURKA/spindle study.
    action: ACCEPT
    reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
    supported_by:
    - *id005
    - *id006
- term:
    id: GO:0001578
    label: microtubule bundle formation
  evidence_type: IMP
  original_reference_id: PMID:26246606
  qualifier: involved_in
  review:
    summary: ALADIN depletion produces shorter, less robust spindles and affects spindle microtubule organization.
    action: KEEP_AS_NON_CORE
    reason: The phenotype supports a role in spindle organization, but microtubule bundle formation is a less direct and less informative description than mitotic spindle assembly/AURKA localization. Keep the row as non-core supporting phenotype rather than the main process term.
    supported_by:
    - *id005
    - *id006
- term:
    id: GO:0072686
    label: mitotic spindle
  evidence_type: IDA
  original_reference_id: PMID:26246606
  qualifier: located_in
  review:
    summary: ALADIN localizes to mitotic spindle structures, including the mitotic spindle, in the AURKA/spindle study.
    action: ACCEPT
    reason: The mitotic localization is experimentally supported and functionally tied to ALADIN-dependent spatial regulation of Aurora A. This is a genuine AAAS role, distinct from but compatible with its NPC identity.
    supported_by:
    - *id005
    - *id006
- term:
    id: GO:0090307
    label: mitotic spindle assembly
  evidence_type: IMP
  original_reference_id: PMID:26246606
  qualifier: involved_in
  review:
    summary: ALADIN is required for robust mitotic spindle formation and timely chromosome alignment through spatial regulation of Aurora A and associated spindle factors.
    action: ACCEPT
    reason: This is directly supported by depletion experiments in human and Drosophila cells and by phenotypes in triple-A patient fibroblasts. It should be retained as a well-supported AAAS biological process.
    supported_by:
    - *id005
    - *id006
- term:
    id: GO:0005643
    label: nuclear pore
  evidence_type: IDA
  original_reference_id: PMID:12730363
  qualifier: part_of
  review:
    summary: AAAS/ALADIN is a nuclear pore complex nucleoporin. Disease-associated ALADIN variants lose NPC targeting, and NDC1 anchoring is required for ALADIN localization at the nuclear envelope.
    action: ACCEPT
    reason: The nuclear pore annotation is a central, well-supported cellular component for AAAS. The PN nuclear-pore projection also agrees with existing GOA, but it adds no new term beyond this already captured location.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id001
    - *id002
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: AAAS was detected in a high-throughput membrane proteomics study, but generic membrane localization is much less informative than nuclear envelope/nuclear pore.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term is not strictly false because the NPC is embedded in the nuclear envelope, but this HDA row loses the important nuclear-pore context and the source study includes many proteins predicted to be transiently associated with membranes.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: AAAS was detected in a sperm nucleus proteomics data set, but generic nucleus localization is broader than the established nuclear pore/nuclear envelope site.
    action: MARK_AS_OVER_ANNOTATED
    reason: The nucleus term is broadly compatible with an NPC protein but over-generalizes the curated AAAS localization. Nuclear pore and nuclear envelope should be preferred for functional interpretation.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: With this approach, 403 different proteins have been identified from the isolated sperm nuclei.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1176059
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-165043
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-165047
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170796
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-180622
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192627
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192925
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2990880
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2990882
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000348
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000399
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3000411
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4551649
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4551679
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4570493
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4615872
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4615987
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4655355
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5228508
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5228523
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252041
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5661474
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6783483
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-75096
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-75097
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-75098
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9614367
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9614369
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9708889
  qualifier: located_in
  review:
    summary: AAAS is correctly placed at the nuclear envelope/NPC, but the Reactome source event should be treated as location context only for this nuclear envelope row.
    action: ACCEPT
    reason: The Reactome row should be interpreted only as cellular-component support for AAAS/ALADIN being part of the nuclear-envelope/NPC machinery. The specific Reactome events range across viral transport, mRNA/tRNA transport, SUMOylation, and disease pathways and should not be used to infer those pathway processes for AAAS without separate gene-level evidence.
    additional_reference_ids:
    - PMID:19782045
    supported_by:
    - reference_id: PMID:19782045
      supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
      reference_section_type: ABSTRACT
- term:
    id: GO:0006913
    label: nucleocytoplasmic transport
  evidence_type: IDA
  original_reference_id: PMID:12730363
  qualifier: acts_upstream_of_or_within
  review:
    summary: ALADIN is an NPC-associated protein implicated in normal nucleocytoplasmic transport rather than gross NPC structure. Existing IBA/NAS/IDA transport rows are consistent with the disease-mutant mislocalization evidence and NPC biology.
    action: ACCEPT
    reason: Nucleocytoplasmic transport is more informative and better scoped for AAAS than the PN-projected broad parent protein transport. I retain this existing transport term and do not add GO:0015031 protein transport from the PN projection.
    additional_reference_ids:
    - PMID:19782045
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id003
    - *id004
- term:
    id: GO:0046822
    label: regulation of nucleocytoplasmic transport
  evidence_type: NAS
  original_reference_id: PMID:12730363
  qualifier: involved_in
  review:
    summary: The original ALADIN disease-mutant study explicitly proposed a regulatory role in nucleocytoplasmic transport.
    action: ACCEPT
    reason: This term is a conservative way to capture ALADIN as an NPC-associated regulator/support factor rather than a transport receptor or cargo-specific transporter. It is preferable to adding broad protein transport from the PN projection.
    additional_reference_ids:
    - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    supported_by:
    - *id003
    - *id004
core_functions:
- description: ALADIN is a scaffold nucleoporin of the nuclear pore complex at the nuclear envelope. Its NDC1-dependent NPC anchoring supports normal NPC-associated nucleocytoplasmic transport; disease-associated variants commonly fail to target to NPCs, linking loss of NPC integration to triple-A syndrome biology.
  directly_involved_in:
  - id: GO:0006913
    label: nucleocytoplasmic transport
  - id: GO:0046822
    label: regulation of nucleocytoplasmic transport
  locations:
  - id: GO:0005635
    label: nuclear envelope
  in_complex:
    id: GO:0005643
    label: nuclear pore
  supported_by:
  - reference_id: PMID:12730363
    supporting_text: A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm.
    reference_section_type: ABSTRACT
  - reference_id: PMID:19782045
    supporting_text: Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated.
    reference_section_type: ABSTRACT
  - reference_id: file:human/AAAS/AAAS-deep-research-falcon.md
    supporting_text: 'Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate.'
- description: During mitosis, ALADIN acts as a spatial regulator of Aurora A localization and associated spindle factors, supporting robust mitotic spindle formation and timely chromosome alignment.
  directly_involved_in:
  - id: GO:0090307
    label: mitotic spindle assembly
  locations:
  - id: GO:0072686
    label: mitotic spindle
  - id: GO:0000922
    label: spindle pole
  supported_by:
  - *id005
  - *id006
  - reference_id: file:human/AAAS/AAAS-deep-research-falcon.md
    supporting_text: 'Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate.'
proposed_new_terms: []
suggested_questions:
- question: Should AAAS be annotated to a more specific nuclear protein import/export term only if future gene-level evidence identifies affected protein cargos, rather than adding the broad PN-projected GO:0015031 protein transport?
  experts:
  - Cronshaw JM
  - Matunis MJ
  - Kind B
  - Huebner A
- question: Is the ALADIN-PGRMC2 association functionally upstream of adrenal steroidogenesis in vivo, or should it remain an interaction note without a GO process annotation?
  experts:
  - Juehlen R
  - Koehler K
  - Huebner A
suggested_experiments:
- hypothesis: ALADIN loss selectively alters nuclear import or export of stress-response or DNA-repair proteins in adrenal and neural cell types.
  description: Perform quantitative nuclear/cytoplasmic proteomics or live import/export reporter assays in AAAS-null and rescue human adrenal/neural cell models, with cargo-level validation for candidate proteins.
  experiment_type: nucleocytoplasmic transport assay
- hypothesis: The ALADIN-PGRMC2 interaction has a specific steroidogenic consequence rather than representing proximity at the perinuclear ER/NPC.
  description: Compare steroidogenic enzyme activity, PGRMC2 localization, and CYP-dependent steroid output in AAAS knockout, NDC1-anchoring-defective rescue, and wild-type rescue adrenocortical cells.
  experiment_type: functional rescue and steroidogenesis assay