AHI1 encodes Jouberin, a multidomain protein containing WD40 repeats, an SH3 domain and an N-terminal interaction region. Jouberin concentrates at the distal mother centriole, ciliary basal body and transition zone, where it associates with the MKS complex and supports cilium formation and the localization of ciliary proteins. Its effects vary with cell type: loss can reduce ciliation or alter the composition and signaling of cilia that remain. Human Joubert-syndrome fibroblasts have reduced ciliation and reduced ciliary ARL13B, while animal models show defects in photoreceptor outer segments and receptor delivery to neuronal cilia. Jouberin interacts with nephrocystin-1, HAP1 and other partners and can self-associate; the precise native oligomeric stoichiometry is unresolved. It also has functions outside the ciliary base. Association with beta-catenin promotes beta-catenin nuclear accumulation and amplifies stimulated canonical Wnt signaling, while ciliary sequestration constrains this activity. In immune-cell models, Jouberin recruits the deubiquitinase OTUD1 to TYK2, maintaining TYK2 stability and type I interferon responsiveness. Biallelic pathogenic AHI1 variants cause Joubert syndrome, with variable retinal and renal involvement.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002092 positive regulation of receptor internalization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ahi1 supports receptor internalization and subsequent TrkB sorting in neurons. Reason: The mouse Q8K3E5 donor IMP traces to PMID:20956301 in the MGI comparative annotation snapshot. The primary full Results include a surface-crosslinking/internalization assay and reduced intracellular BDNF after Ahi1 depletion, as well as accelerated degradation of internalized TrkB. Thus internalization was actually investigated. Retain the orthology inference as a neuronal trafficking context; the degradation assay alone would not establish internalization, and the phenotype is not evidence that AHI1 is itself an endocytic receptor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) - the 1:1 orthologue SUPPORTS TRANSFER The mouse Q8K3E5 donor IMP traces to PMID:20956301 in the MGI comparative annotation snapshot. The primary full Results include a surface-crosslinking/internalization assay and reduced intracellular BDNF after Ahi1 depletion, as well as accelerated degradation of internalized TrkB. Thus internalization was actually investigated. Retain the orthology inference as a neuronal trafficking context; the degradation assay alone would not establish internalization, and the phenotype is not evidence that AHI1 is itself an endocytic receptor. Supporting Evidence: PMID:20956301 Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. |
| GO:0005515 protein binding | IPI PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | REMOVE | Summary: NPHP1 association is supported, but generic protein binding is not an informative functional annotation. Reason: The source supports AHI1βNPHP1 association by endogenous and exogenous co-immunoprecipitation in HEK293 cells. This decision removes the uninformative GO:0005515 summary, not the interaction. Domain-specific binding and complex organization remain biologically relevant, but the source-specific experiments summarized here do not establish an adaptor reaction between two ciliary partners. A precise interaction-domain annotation can be reconsidered with the original domain-mapping experiment. Supporting Evidence: PMID:18633336 We show that Jouberin interacts with nephrocystin-1 as determined by yeast-2-hybrid system and this was confirmed by exogenous and endogenous co-immunoprecipitation in HEK293 cells. |
| GO:0005515 protein binding | IPI PMID:22623184 Molecular and structural characterization of the SH3 domain ... | REMOVE | Summary: The AHI1βDNM2 interaction does not make generic protein binding a useful functional summary. Reason: PMID:22623184 reports that the AHI1 SH3 domain interacts with dynamin-2 and links SH3 deletion to TKI responses in BCR-ABL-positive cells. The cached abstract does not resolve the complete binding assay or a specific regulation of DNM2 catalysis. Remove the generic binding annotation without denying the experimentally curated interaction; do not infer GTPase regulation or ciliary adaptor activity from binding alone. |
| GO:0005515 protein binding | IPI PMID:23532844 The Joubert syndrome-associated missense mutation (V443D) in... | REMOVE | Summary: NPHP1 association is supported, but generic protein binding is not an informative functional annotation. Reason: The source supports AHI1βNPHP1 association by co-immunoprecipitation and co-migration of human constructs, with altered interaction for V443D. This decision removes the uninformative GO:0005515 summary, not the interaction. Domain-specific binding and complex organization remain biologically relevant, but the source-specific experiments summarized here do not establish an adaptor reaction between two ciliary partners. A precise interaction-domain annotation can be reconsidered with the original domain-mapping experiment. Supporting Evidence: PMID:23532844 AHI1-WT and NPHP1 co-migrated in two different size complexes, corresponding to molecular masses of 430 and 210 kDa |
| GO:0005515 protein binding | IPI PMID:23532844 The Joubert syndrome-associated missense mutation (V443D) in... | REMOVE | Summary: HAP1 binding and mutual stabilization are supported; generic protein binding adds no specific molecular function. Reason: PMID:23532844 maps HAP1 association to AHI1 residues 141β434 and demonstrates altered binding and protein stability. Its HAP1-null neuronal and fibroblast experiments do not show an equivalent ciliary requirement. Retain these findings in the biological account, but remove the generic binding annotation without treating the interaction as false or assigning an untested ciliary bridging role. Supporting Evidence: PMID:23532844 We determined that a smaller region of AHI1-F2, denoted as AHI1-F3 (141β434 aa), is still able to bind HAP1 |
| GO:0005515 protein binding | IPI PMID:25825872 Preferred SH3 domain partners of ADAM metalloproteases inclu... | MODIFY | Summary: The isolated AHI1 SH3 domain recognizes proline-rich ADAM12 tail sequences. Reason: The phage-display and peptide-array experiments in PMID:25825872 positively establish domain-level recognition of proline-rich motifs. GO:0070064 describes this binding specificity more informatively than generic protein binding. Shared motif preferences across several SH3 domains do not invalidate the positive AHI1 assay. The result concerns an isolated domain and does not establish a full-length AHI1βADAM12 complex in cells or a physiological ADAM12-regulatory role. Proposed replacements: proline-rich region binding Supporting Evidence: PMID:25825872 ADAM12, a strong nephrocystin binder, also selected the SH3 domain of another ciliary disease-associated protein AHI1/Jouberin |
| GO:0005813 centrosome | IDA GO_REF:0000052 | ACCEPT | Summary: Centrosomal or centriolar localization is consistent with AHI1 ciliary organization. Reason: The HPA-curated IDA directly records centrosomal localization in human cells. The source is retained at its observed resolution; no unverified conversion of every centrosomal pool to transition zone is required. |
| GO:0005813 centrosome | IDA PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | ACCEPT | Summary: Centrosomal or centriolar localization is consistent with AHI1 ciliary organization. Reason: PMID:18633336 reports centrosomal Jouberin-GFP in MDCK cells and endogenous ciliary-base localization in mIMCD3 cells. A host-cell species alone does not establish the species of an exogenous construct. The full original construct details are not available locally, but later explicitly human AHI1 constructs in PMID:23532844 independently support basal-body localization, consistent with the broader centrosome annotation. Supporting Evidence: PMID:18633336 a Jouberin-GFP construct localized to centrosomes in subconfluent and dividing MDCK cells. |
| GO:0005814 centriole | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosomal or centriolar localization is consistent with AHI1 ciliary organization. Reason: The UniProt subcellular-location mapping to centriole is consistent with mother-centriole and basal-body imaging in mouse Ahi1 studies and independently with human AHI1 construct localization. The vocabulary mapping itself provides no new localization experiment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0046 Β· Centriole SUPPORTS TRANSFER UniProt subcellular-location vocabulary source carried by the original IEA. The mapping is biologically consistent with the reviewed localization experiments, but is not an independent measurement. |
| GO:0005814 centriole | ISS GO_REF:0000024 | ACCEPT | Summary: Centrosomal or centriolar localization is consistent with AHI1 ciliary organization. Reason: The mouse Q8K3E5 donor is experimentally localized to the mother centriole in PMID:19625297. This conserved localization agrees with human AHI1 basal-body imaging in PMID:23532844. Centriole is a correct source-level compartment even though more precise locations are separately available. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse Q8K3E5 donor is experimentally localized to the mother centriole in PMID:19625297. This conserved localization agrees with human AHI1 basal-body imaging in PMID:23532844. Centriole is a correct source-level compartment even though more precise locations are separately available. Supporting Evidence: PMID:19625297 Ahi1 immunostaining mapped to the base of the primary non-motile cilium, specifically the basal body |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | ACCEPT | Summary: The cytosolic compartment is compatible with AHI1-containing ciliary-base assemblies. Reason: Reactome places AHI1 within a cytosolic basal-body/transition-zone participant in RAB3IP-mediated nucleotide exchange on RAB8A. This is a curated participant-compartment assertion, not a direct microscopy assay or an assertion that AHI1 catalyzes the named reaction. Cytoplasmic AHI1 and its ciliary-base assemblies support the broad compartment. Retain it at the modeled resolution; a transition-zone replacement would imply greater spatial precision than this source independently provides. Independent imaging in PMID:28442542 shows diffuse cytoplasmic human mRFP-AHI1 in hTERT-RPE1 cells. This corroborates the broad cellular pool without resolving cytosol from every cytoplasmic subcompartment; the cytosol assertion remains supported at Reactome participant resolution. Supporting Evidence: PMID:28442542 Wild-type mRFP-AHI1 showed a diffused cytoplasmic localisation and a strong enrichment at the ciliary base of ciliated hTERT-RPE1 cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | ACCEPT | Summary: The cytosolic compartment is compatible with AHI1-containing ciliary-base assemblies. Reason: Reactome places AHI1 within a cytosolic basal-body/transition-zone participant in recruitment of transition-zone proteins. This is a curated participant-compartment assertion, not a direct microscopy assay or an assertion that AHI1 catalyzes the named reaction. Cytoplasmic AHI1 and its ciliary-base assemblies support the broad compartment. Retain it at the modeled resolution; a transition-zone replacement would imply greater spatial precision than this source independently provides. Independent imaging in PMID:28442542 shows diffuse cytoplasmic human mRFP-AHI1 in hTERT-RPE1 cells. This corroborates the broad cellular pool without resolving cytosol from every cytoplasmic subcompartment; the cytosol assertion remains supported at Reactome participant resolution. Supporting Evidence: PMID:28442542 Wild-type mRFP-AHI1 showed a diffused cytoplasmic localisation and a strong enrichment at the ciliary base of ciliated hTERT-RPE1 cells |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | ACCEPT | Summary: The cytosolic compartment is compatible with AHI1-containing ciliary-base assemblies. Reason: Reactome places AHI1 within a cytosolic basal-body/transition-zone participant in CEP164-dependent recruitment of RAB3IP-carrying vesicles. This is a curated participant-compartment assertion, not a direct microscopy assay or an assertion that AHI1 catalyzes the named reaction. Cytoplasmic AHI1 and its ciliary-base assemblies support the broad compartment. Retain it at the modeled resolution; a transition-zone replacement would imply greater spatial precision than this source independently provides. Independent imaging in PMID:28442542 shows diffuse cytoplasmic human mRFP-AHI1 in hTERT-RPE1 cells. This corroborates the broad cellular pool without resolving cytosol from every cytoplasmic subcompartment; the cytosol assertion remains supported at Reactome participant resolution. Supporting Evidence: PMID:28442542 Wild-type mRFP-AHI1 showed a diffused cytoplasmic localisation and a strong enrichment at the ciliary base of ciliated hTERT-RPE1 cells |
| GO:0005911 cell-cell junction | IDA PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | KEEP AS NON CORE | Summary: Jouberin localizes to epithelial cell junctions as well as the ciliary base. Reason: PMID:18633336 reports junctional localization in mouse mIMCD3 cells; its full construct-specific details were not recovered. Independently, PMID:23532844 directly follows explicitly human AHI1 constructs at cellβcell junctions in the same host-cell type, with localization defects for disease variants. Retain this epithelial localization as a contextual pool rather than replacing it with the ciliary transition zone. Supporting Evidence: PMID:18633336 Jouberin is expressed at cell-cell junctions, primary cilia and basal body of mIMCD3 cells PMID:23532844 whereas more than 60% of the cells expressing AHI1-WT had AHI1 localized to the cell junctions of IMCD3 cells |
| GO:0005912 adherens junction | IDA PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | KEEP AS NON CORE | Summary: Jouberin localizes to epithelial cell junctions as well as the ciliary base. Reason: PMID:18633336 reports junctional localization in mouse mIMCD3 cells; its full construct-specific details were not recovered. Independently, PMID:23532844 directly follows explicitly human AHI1 constructs at cellβcell junctions in the same host-cell type, with localization defects for disease variants. Retain this epithelial localization as a contextual pool rather than replacing it with the ciliary transition zone. Supporting Evidence: PMID:18633336 Jouberin is expressed at cell-cell junctions, primary cilia and basal body of mIMCD3 cells |
| GO:0005912 adherens junction | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Jouberin localizes to epithelial cell junctions as well as the ciliary base. Reason: The UniProt location-vocabulary mapping is consistent with the experimentally observed junctional pool in PMID:18633336 and human AHI1 constructs in PMID:23532844. Retain this epithelial localization as a contextual pool rather than replacing it with the ciliary transition zone. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0009 Β· Cell junction, adherens junction SUPPORTS TRANSFER UniProt subcellular-location vocabulary source carried by the original IEA. The mapping is biologically consistent with the reviewed localization experiments, but is not an independent measurement. |
| GO:0005929 cilium | IC PMID:21959375 Modelling a ciliopathy: Ahi1 knockdown in model systems reve... | ACCEPT | Summary: Ciliary localization belongs to the principal AHI1 biological role. Reason: The IC source PMID:21959375 studies mouse IMCD3 cells and zebrafish and supports ciliary association and function; it is not itself a direct human localization assay. Independent PMID:23532844 images a human construct in mouse cells. PMID:28442542 provides a separate human construct in human hTERT-RPE1 cells: sequence-validated full-length isoform 1, expressed as an N-terminal mRFP fusion, is enriched at the ciliary base. This corroborates the cilium-associated basal-body pool without establishing distribution throughout the ciliary axoneme. Preserve the original IC source and experimental-species distinction. Supporting Evidence: PMID:23532844 These results showed that βΌ80% of the cells expressing the wild type AHI1 (AHI1-WT) protein had AHI1 at the basal body of the primary cilium PMID:28442542 Wild-type mRFP-AHI1 showed a diffused cytoplasmic localisation and a strong enrichment at the ciliary base of ciliated hTERT-RPE1 cells |
| GO:0005929 cilium | IDA PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | ACCEPT | Summary: Ciliary localization belongs to the principal AHI1 biological role. Reason: The abstract of PMID:18633336 explicitly describes primary-cilium and basal-body staining in mouse mIMCD3 cells. Later human-construct imaging in PMID:23532844 corroborates the ciliary-base pool. The full original construct details were not recovered, so host species alone is not used to declare a wrong-gene annotation. Supporting Evidence: PMID:18633336 Jouberin is expressed at cell-cell junctions, primary cilia and basal body of mIMCD3 cells |
| GO:0005929 cilium | ISS GO_REF:0000024 | ACCEPT | Summary: Ciliary localization belongs to the principal AHI1 biological role. Reason: The mouse Q8K3E5 donor has direct ciliary imaging in PMID:19625297 and related studies. Human construct localization and Joubert-fibroblast ciliary defects independently support transfer. The broad cilium term is a valid location and does not require uniform staining of the entire axoneme. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse Q8K3E5 donor has direct ciliary imaging in PMID:19625297 and related studies. Human construct localization and Joubert-fibroblast ciliary defects independently support transfer. The broad cilium term is a valid location and does not require uniform staining of the entire axoneme. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ahi1 preserves TrkB-dependent receptor-tyrosine-kinase signaling in neurons. Reason: The Q8K3E5 donor IMP is PMID:20956301, verified in the MGI comparative snapshot. Ahi1 loss changes TrkB trafficking and stability and reduces downstream AKT/ERK signaling; the primary study includes receptor/ligand internalization experiments. AHI1 participates through receptor handling rather than kinase catalysis. Retain the mammalian orthology inference as a neuronal signaling context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The Q8K3E5 donor IMP is PMID:20956301, verified in the MGI comparative snapshot. Ahi1 loss changes TrkB trafficking and stability and reduces downstream AKT/ERK signaling; the primary study includes receptor/ligand internalization experiments. AHI1 participates through receptor handling rather than kinase catalysis. Retain the mammalian orthology inference as a neuronal signaling context. |
| GO:0008104 intracellular protein localization | ISS GO_REF:0000024 | MODIFY | Summary: The localization evidence supports ciliary cargo delivery more precisely than general intracellular protein localization. Reason: The historical mouse donor GO:0008104 IGI in PMID:20081859 concerns mislocalized opsin and the photoreceptor outer segment, a modified cilium. Independent human Joubert-fibroblast ARL13B measurements in PMID:23532844 and mouse neuronal MCHR1 trafficking in PMID:33741721 identify the same ciliary destination. Replace this broad process with GO:0061512; this does not imply that all AHI1-dependent trafficking is ciliary. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The historical mouse donor GO:0008104 IGI in PMID:20081859 concerns mislocalized opsin and the photoreceptor outer segment, a modified cilium. Independent human Joubert-fibroblast ARL13B measurements in PMID:23532844 and mouse neuronal MCHR1 trafficking in PMID:33741721 identify the same ciliary destination. Replace this broad process with GO:0061512; this does not imply that all AHI1-dependent trafficking is ciliary. Proposed replacements: protein localization to cilium Supporting Evidence: PMID:23532844 JBTS fibroblasts displayed a significant reduction in ARL13B ciliary localization in their remaining primary cilia as compared with ARL13B ciliary localization in normal fibroblasts PMID:19625297 In contrast, in Ahi1-knockdown cells, Rab8a expression was significantly lower, and it could not be detected at the basal body |
| GO:0016192 vesicle-mediated transport | ISS GO_REF:0000024 | ACCEPT | Summary: Vesicular trafficking is a supported component of AHI1 cargo-localization biology. Reason: The mouse Q8K3E5 donor is grounded in PMID:19625297: cholera-toxin-B-positive vesicles fail to reach the Golgi efficiently and transferrin recycling is impaired after Ahi1 depletion. Vesicle formation and internalization are not globally absent. Together with Rab8a stabilization/localization and ciliary cargo phenotypes, these results support the broad transport process by orthology; the evidence spans routes and does not justify narrowing every assay to a single cargo. Vesicular cargo organization is part of the principal cellular role summarized in the ciliary/trafficking core; source-specific refinement of a separate opsin-localization annotation does not make this multi-route transport evidence non-core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse Q8K3E5 donor is grounded in PMID:19625297: cholera-toxin-B-positive vesicles fail to reach the Golgi efficiently and transferrin recycling is impaired after Ahi1 depletion. Vesicle formation and internalization are not globally absent. Together with Rab8a stabilization/localization and ciliary cargo phenotypes, these results support the broad transport process by orthology; the evidence spans routes and does not justify narrowing every assay to a single cargo. Supporting Evidence: PMID:19625297 Whereas control cells recycled the Tf/TfR back to the plasma membrane after 60 min, Ahi1-knockdown cells accumulated Tf/TfR vesicles in the perinuclear region, indicating that vesicle recycling to the plasma membrane is disrupted |
| GO:0035845 photoreceptor cell outer segment organization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ahi1 supports photoreceptor outer-segment morphogenesis in a specialized ciliary context. Reason: The Q8K3E5 donor carries IMP evidence from PMID:20592197 and IGI evidence from PMID:20081859. Ahi1-null photoreceptors fail to form outer segments and mislocalize opsin before substantial cell death. These developmental organization measurements support a specialized retinal role distinct from a general claim of apoptosis control. Human transfer is orthological rather than a direct human-retina experiment. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The Q8K3E5 donor carries IMP evidence from PMID:20592197 and IGI evidence from PMID:20081859. Ahi1-null photoreceptors fail to form outer segments and mislocalize opsin before substantial cell death. These developmental organization measurements support a specialized retinal role distinct from a general claim of apoptosis control. Human transfer is orthological rather than a direct human-retina experiment. Supporting Evidence: PMID:20081859 We show that Ahi1-null mice fail to form retinal outer segments and have abnormal distribution of opsin throughout their photoreceptors. |
| GO:0035869 ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: AHI1 is associated with the ciliary transition zone. Reason: PMID:22179047 identifies Ahi1 in the transition-zone complex by affinity purification and co-fractionation in mouse systems. Independent superresolution imaging in PMID:25103236 places Ahi1 in a ring near the distal centriole, and human construct and patient-cell data in PMID:23532844 support the conserved ciliary-base function. Preserve the NAS source rather than relabeling the underlying assay as human IDA. Supporting Evidence: PMID:25103236 We show that Cby1, Ofd1, and Ahi1 localize as tightly apposed rings at a similar position along the long axis of the centriole. |
| GO:0036038 MKS complex | ISS GO_REF:0000024 | ACCEPT | Summary: AHI1 is a subunit of the MKS transition-zone complex. Reason: The mouse orthology source Q8K3E5 is consistent with PMID:22179047, whose affinity purifications and co-fractionation recover Ahi1 within the transition-zone assembly. Structural membership can be supported even when the disruption experiments target other subunits. This membership does not by itself specify an AHI1-mediated molecular bridge or prove every complex-level process for the individual subunit. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse orthology source Q8K3E5 is consistent with PMID:22179047, whose affinity purifications and co-fractionation recover Ahi1 within the transition-zone assembly. Structural membership can be supported even when the disruption experiments target other subunits. This membership does not by itself specify an AHI1-mediated molecular bridge or prove every complex-level process for the individual subunit. |
| GO:0036038 MKS complex | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | ACCEPT | Summary: AHI1 is a subunit of the MKS transition-zone complex. Reason: The NAS citation points to PMID:22179047, whose affinity purifications and co-fractionation recover Ahi1 within the transition-zone assembly. Structural membership can be supported even when the disruption experiments target other subunits. This membership does not by itself specify an AHI1-mediated molecular bridge or prove every complex-level process for the individual subunit. |
| GO:0036064 ciliary basal body | IBA GO_REF:0000033 | ACCEPT | Summary: The PAINT ancestral basal-body localization agrees with direct AHI1/Ahi1 imaging. Reason: The IBA descends from PTN002893387. Experimental descendant grounding includes human AHI1 and mouse Ahi1 basal-body localization; the target appearing among descendant evidence is expected, not circular. The current PAINT family slice could not be downloaded because of DNS failure, so its detailed node placement/MSA was not independently reconstructed. Direct human construct imaging in PMID:23532844 and mouse imaging in PMID:19625297 independently support the conserved location. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002893387 Β· PTN002893387 UNRESOLVED Ancestral node recorded by the seeded IBA. The current PAINT tree/MSA slice could not be retrieved (DNS failure), so its internal placement is not independently reconstructed. Retention rests on the curator's ancestral inference and independently reviewed descendant evidence; there is no demonstrated target-specific loss. Supporting Evidence: PMID:19625297 Ahi1 immunostaining mapped to the base of the primary non-motile cilium, specifically the basal body |
| GO:0036064 ciliary basal body | IDA PMID:18633336 Jouberin localizes to collecting ducts and interacts with ne... | ACCEPT | Summary: The ciliary basal body is an established AHI1 location. Reason: PMID:18633336 reports basal-body Jouberin in mouse mIMCD3 cells; the locally available abstract does not resolve all original construct details. PMID:23532844 independently demonstrates human AHI1 localization in that mouse host. PMID:28442542 further images sequence-validated full-length human AHI1 isoform 1 as an N-terminal mRFP fusion in human hTERT-RPE1 cells, directly corroborating ciliary-base enrichment. The additional human experiment strengthens the location while leaving the original IDA source and its construct-access boundary unchanged. Supporting Evidence: PMID:23532844 These results showed that βΌ80% of the cells expressing the wild type AHI1 (AHI1-WT) protein had AHI1 at the basal body of the primary cilium PMID:28442542 RP-associated and Joubert syndrome-associated missense variants in AHI1 caused a significant decrease in Jouberin enrichment to the basal bodies of cilia in hTERT-RPE1 cells, compared with wild-type Jouberin |
| GO:0042802 identical protein binding | IPI PMID:23532844 The Joubert syndrome-associated missense mutation (V443D) in... | ACCEPT | Summary: Human AHI1 self-associates, with unresolved native oligomeric stoichiometry. Reason: PMID:23532844 co-immunoprecipitates differently tagged human AHI1 copies in HEK293 cells. V443D retains self-association despite disrupting larger partner-containing assemblies. This supports identical protein binding; migration-based candidate dimer/tetramer assignments do not establish a unique physiological stoichiometry. Self-association is integrated with the ciliary organization role rather than treated as an independent biological program. Supporting Evidence: PMID:23532844 These results demonstrate that AHI1 is capable of self-association; however, the V443D mutation in AHI1 did not disrupt the self-association of AHI1 PMID:23532844 which could correspond to an AHI1 homodimer. However, the molecular weight of the peak is smaller than the expected weight of the dimer |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ahi1-dependent photoreceptor protein handling supports cell survival in a retinal context. Reason: The mouse Q8K3E5 IMP from PMID:20081859 is a real curated phenotype: Ahi1 loss causes opsin mislocalization followed by caspase-positive photoreceptor death. Lowering opsin dosage delays death without restoring outer segments, locating the survival effect downstream of cargo organization. That causal ordering does not disprove negative regulation of apoptosis, which need not be direct caspase inhibition. Retain the orthology inference as a contextual consequence, not a core anti-apoptotic molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse Q8K3E5 IMP from PMID:20081859 is a real curated phenotype: Ahi1 loss causes opsin mislocalization followed by caspase-positive photoreceptor death. Lowering opsin dosage delays death without restoring outer segments, locating the survival effect downstream of cargo organization. That causal ordering does not disprove negative regulation of apoptosis, which need not be direct caspase inhibition. Retain the orthology inference as a contextual consequence, not a core anti-apoptotic molecular activity. Supporting Evidence: PMID:20081859 Apoptotic cell death of photoreceptors occurs rapidly between 2 and 4 weeks of age in these mice and is significantly (P = 0.00175 and 0.00613) delayed by a reduced dosage of opsin. |
| GO:0044458 motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the ancestral inference of participation in motile-cilium assembly. Reason: PTN002893387 represents a PAINT ancestral assertion rather than a pairwise transfer. PMID:21959375 directly shows loss of Kupffer's-vesicle cilia after zebrafish ahi1 knockdown, together with laterality defects; mouse Ahi1 mRNA rescues gross morphant phenotypes. The study also places Ahi1 broadly in ciliated eukaryotes. A human non-motile-cilium annotation does not exclude a conserved role in assembling motile cilia, and there is no target-specific loss evidence here. The current PAINT slice could not be retrieved, so retain the curator's phylogenetic judgment without claiming a directly measured native human motile-cilium phenotype. The recovered primary full text and Figure 10 for PMID:28118669 report rescue of mutant zebrafish pronephric cilia by human AHI1 RNA, supporting conservation across vertebrates. This cilium-assembly role is included within the broader GO:0060271 core process; a core summary need not repeat each supported descendant. Neither donor count nor the UniProt review status of a zebrafish entry is evidence against this inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002893387 Β· PTN002893387 UNRESOLVED Ancestral node recorded by the seeded IBA. The current PAINT tree/MSA slice could not be retrieved (DNS failure), so its internal placement is not independently reconstructed. Retention rests on the curator's ancestral inference and independently reviewed descendant evidence; there is no demonstrated target-specific loss. Supporting Evidence: PMID:21959375 cilia were absent from KV in 23 out of 25 (92%) cldnb :Lyn-GFP embryos following ahi1 MO injection PMID:28118669 Injection of 100 pg of wild-type AHI1 mRNA resulted in increased numbers of cilia in the distal kidney of ahi1lri46 mutants when compared to embryos injected with vehicle or those injected with the AHI1r589X mRNA (Figs. 10AβE). |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: AHI1 can promote transcriptional output through signaling rather than direct DNA recognition. Reason: The MGI comparative snapshot verifies the mouse Q8K3E5 IMP from PMID:20956301, but the exact transcription readout underlying that donor assertion remains unresolved after the cached abstract and externally recovered Results inspected here. Independently, PMID:19718039 demonstrates potentiation of Wnt-stimulated reporter and endogenous cyclin D1 expression with beta-catenin nuclear accumulation; PMID:21623382 supports the Wnt response in vivo. Absence of a DNA-binding domain does not refute a positive-regulation process. Retain the broad, context-dependent process without assigning sequence-specific transcription-factor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The MGI comparative snapshot verifies the mouse Q8K3E5 IMP from PMID:20956301, but the exact transcription readout underlying that donor assertion remains unresolved after the cached abstract and externally recovered Results inspected here. Independently, PMID:19718039 demonstrates potentiation of Wnt-stimulated reporter and endogenous cyclin D1 expression with beta-catenin nuclear accumulation; PMID:21623382 supports the Wnt response in vivo. Absence of a DNA-binding domain does not refute a positive-regulation process. Retain the broad, context-dependent process without assigning sequence-specific transcription-factor activity. Supporting Evidence: PMID:19718039 measurement of endogenous expression of the Wnt target cyclin D1 (ref. 41) revealed augmentation of the transcription response similar to that seen in the luciferase assay |
| GO:0050795 regulation of behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ahi1 affects behavior through neuronal signaling and receptor trafficking. Reason: The mouse Q8K3E5 IMP from PMID:20956301 is verified in the MGI comparative snapshot. Neuronal Ahi1 depletion changes forced-swim and tail-suspension outcomes alongside TrkB trafficking/signaling defects, and TrkB replacement or antidepressant treatment ameliorates the behavioral outcome. This is a real mammalian regulatory phenotype; its organism-level nature does not alone make it invalid. Retain it as non-core and do not equate these mouse assays with a directly demonstrated human psychiatric mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse Q8K3E5 IMP from PMID:20956301 is verified in the MGI comparative snapshot. Neuronal Ahi1 depletion changes forced-swim and tail-suspension outcomes alongside TrkB trafficking/signaling defects, and TrkB replacement or antidepressant treatment ameliorates the behavioral outcome. This is a real mammalian regulatory phenotype; its organism-level nature does not alone make it invalid. Retain it as non-core and do not equate these mouse assays with a directly demonstrated human psychiatric mechanism. |
| GO:0060271 cilium assembly | IMP PMID:21959375 Modelling a ciliopathy: Ahi1 knockdown in model systems reve... | ACCEPT | Summary: Cilium assembly is supported by model-system perturbation and independent human patient-cell evidence. Reason: The full PMID:21959375 experiments are mouse IMCD3 siRNA and zebrafish knockdown/rescue. Preserve the seeded human IMP and note this species/code provenance for curator review. The biological assertion is independently supported by reduced ciliation in human AHI1-mutant fibroblasts in PMID:23532844. Tissue and allele differences in the extent of ciliation loss do not negate a role in assembly; AHI1 is not universally essential for every cilium to form. Supporting Evidence: PMID:21959375 In contrast to wild-type (data not shown) and negative control siRNA-transfected cells, ciliary formation was reduced in Ahi1 -silenced cells PMID:23532844 Fibroblasts from individuals with JBTS showed an βΌ50% decrease in primary cilia formation |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse ciliogenesis evidence supports a conserved AHI1 role in cilium assembly. Reason: The Q8K3E5 donor has experimentally curated assembly annotations from PMID:19625297, PMID:20592197 and PMID:21959375. The affected systems include renal cells and photoreceptors; other neuronal and renal contexts retain cilia but show composition/signaling defects. Human Joubert-fibroblast ciliation in PMID:23532844 independently supports transfer. Retain the process without claiming universal obligate assembly dependence. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The Q8K3E5 donor has experimentally curated assembly annotations from PMID:19625297, PMID:20592197 and PMID:21959375. The affected systems include renal cells and photoreceptors; other neuronal and renal contexts retain cilia but show composition/signaling defects. Human Joubert-fibroblast ciliation in PMID:23532844 independently supports transfer. Retain the process without claiming universal obligate assembly dependence. |
| GO:0097730 non-motile cilium | ISS GO_REF:0000024 | ACCEPT | Summary: AHI1 occupies the basal region of primary non-motile cilia. Reason: The mouse donor localization in PMID:19625297 is consistent with the primary-cilium base and with explicitly human AHI1 localization in PMID:23532844. This is a positive localization claim, not an exclusivity statement about all cilium types or a contradiction of the motile-cilium assembly IBA. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K3E5 Β· Mus musculus Ahi1, Jouberin (Swiss-Prot, 1047 aa) SUPPORTS TRANSFER The mouse donor localization in PMID:19625297 is consistent with the primary-cilium base and with explicitly human AHI1 localization in PMID:23532844. This is a positive localization claim, not an exclusivity statement about all cilium types or a contradiction of the motile-cilium assembly IBA. Supporting Evidence: PMID:19625297 Ahi1 immunostaining mapped to the base of the primary non-motile cilium, specifically the basal body |
| GO:1904491 protein localization to ciliary transition zone | NAS PMID:22179047 A ciliopathy complex at the transition zone protects the cil... | UNDECIDED | Summary: Complex membership is established; AHI1-specific participation in maintaining proteins at the transition zone remains insufficiently resolved. Reason: GO:1904491 includes transport to or maintenance within the transition zone. The complex in PMID:22179047 has interdependent subunit localization, and Ahi1 is genuinely recovered as a member; therefore absence of an Ahi1 knockout in that paper is not by itself a reason to reject structural participation. However, the resolved AHI1-specific cargo experiments chiefly measure delivery into the ciliary membrane, not localization of other proteins within the transition zone. PMID:25103236 places Ahi1 downstream of Cby1 recruitment, and the recovered full text of PMID:28118669 reports preserved Cc2d2a/Cep290 connecting-cilium localization in mutant zebrafish photoreceptors, although Cc2d2a signal intensity is reduced. Those contextual findings do not exclude other substrates or tissues. Retain uncertainty about this exact process rather than declaring the complex projection false. The full original NAS source and an AHI1-specific dependency for transition-zone recruitment remain incompletely resolved; the negative results for two proteins in one retinal model do not establish over-annotation across all transition-zone substrates. |
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Download this section (compressed HTML)Q: Can the original human GO:0060271 IMP provenance from PMID:21959375 be reconciled with its mouse/zebrafish experimental systems, or should independent human fibroblast evidence from PMID:23532844 supply the direct experimental source?
Q: Which transition-zone proteins require AHI1 for transport to or maintenance at that zone, as distinct from delivery into the ciliary membrane? Complex membership can support structural participation, but the exact GO:1904491 contribution remains unresolved.
Q: Which tissue, allele and genetic-background differences explain preservation of cilia in some Ahi1-null models and assembly failure in others?
Q: Can the original Jouberin expression-construct records resolve direct-human coding of beta-catenin binding and support coordinated mouse/human curation of the Wnt process? The proposed GO:0090263 ISS requires an established donor assertion or direct human experimental provenance; the measured response remains part of the biological synthesis.
Q: Can mouse OTUD1βTYK2 recruitment in PMID:35821088 be curated for the donor, or can the corresponding AHI1-dependent bridge be demonstrated directly in human cells? Human A549 association and TYK2 stability alone do not establish the specific bridging dependency needed to recode the prior GO:0030674 proposal as direct human IDA/IMP.
Q: Does the PAINT alignment/tree provide additional functional conservation or divergence evidence around PTN002893387? The present source-access limitation should not be interpreted as evidence against the ancestral motile-cilium inference.
Experiment: Measure ciliary composition and transition-zone subunit recruitment after AHI1 deletion and wild-type/domain-mutant rescue in human ciliated cells, distinguishing cilium number from cargo concentration.
Experiment: Determine native or purified AHI1 oligomeric stoichiometry and simultaneous partner occupancy using quantitative structural or biophysical assays.
Experiment: Test AHI1-dependent OTUD1βTYK2 association in human macrophages, separating changes in abundance from changes in association.
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