G patch domain-containing protein 11 (also CCDC75; historically nicknamed CENP-Y), a member of the GPATCH family of glycine-rich G-patch motif proteins that cooperate with DEAH-box RNA helicases to remodel ribonucleoprotein complexes during pre-mRNA splicing. GPATCH11 localizes diffusely in the nucleoplasm with additional signal at the centrosome and acts as a regulator of pre-mRNA splicing; the Schizosaccharomyces pombe ortholog Sap34 binds U2 snRNP and U4/U6·U5 tri-snRNP components and activates the DEAH-box helicase Prp43 via its G-patch domain, and loss of Sap34 causes a global splicing defect with increased intron retention. Biallelic loss-of-function variants in human GPATCH11 (notably the recurrent c.328+1G>T splice variant, which removes the G-patch domain) cause a syndrome of early-onset retinal dystrophy with neurological impairment and craniofacial/skeletal features, with mouse and patient-derived data implicating mis-splicing, altered primary-cilium-associated gene expression, and impaired photoreceptor function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0000776
kinetochore
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: PAINT IBA propagated from the single IDA in PMID:20813266. The upstream GO curators have flagged this annotation (geneontology/go-annotation#6450) as incorrect because the only experimental source is a low-resolution image from a large-scale mitotic-chromosome proteomic screen, and the dedicated 2024 patient/mouse study (PMID:39572588) explicitly reports nucleoplasmic and centrosomal localization with no kinetochore signal. The S. pombe ortholog Sap34 (PMID:42260140) is a spliceosome-associated protein interacting with U2 and tri-snRNP components, not a kinetochore protein. The phylogenetic propagation should be retracted in step with the IDA.
Reason: Propagated by PAINT from a disputed IDA; the IBA inherits the same over-annotation problem. Functional evidence across human, mouse, and fission yeast converges on a pre-mRNA splicing role, not a kinetochore role.
Proposed replacements:
nucleoplasm
centrosome
Supporting Evidence:
PMID:39572588
a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization
PMID:42260140
Sap34 forms a complex with components of the U2 small nuclear ribonucleoprotein (snRNP) and the U4/U6 × U5 tri-snRNP, which are required for early spliceosome assembly and activation
file:human/GPATCH11/GPATCH11-deep-research-falcon.md
GPATCH11 localizes exclusively to centrosomes with no detectable localization at kinetochores or centromeres
|
|
GO:0003676
nucleic acid binding
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: InterPro-derived IEA from the G-patch domain (IPR000467). The G-patch motif is a well-established RNA-binding/helicase-cofactor module, so this annotation is correct in spirit but very general. The patient/mouse study (PMID:39572588) and the S. pombe ortholog characterization (PMID:42260140) both implicate GPATCH11/Sap34 in pre-mRNA binding and spliceosome remodeling. Accept as a non-core, broad MF; more specific successor terms below.
Reason: Domain-based IEA from G-patch (IPR000467); biologically consistent with the protein's spliceosomal role but not informative on its own. The falcon deep-research synthesis reinforces the family-level interpretation that the G-patch motif acts as a DEAH/RHA-box RNA-helicase cofactor rather than a catalytic enzyme, i.e. the nucleic-acid-binding role is exercised in the context of helicase regulation during spliceosome remodeling.
Supporting Evidence:
file:human/GPATCH11/GPATCH11-deep-research-falcon.md
is predicted to act as a cofactor for DEAH-box RNA helicases, which are ATP-dependent enzymes involved in RNA remodeling
|
|
GO:0005515
protein binding
|
IPI
PMID:25416956 A proteome-scale map of the human interactome network. |
KEEP AS NON CORE |
Summary: IntAct annotation derived from large-scale interactome mapping (Rolland et al. 2014) with partners SDCBP (O00560) and ADGRB3 (O60242). Per project guidance, "protein binding" is uninformative and these interactors are not mechanistically linked to GPATCH11's spliceosomal function. Keep the interaction-level evidence but mark non-core.
Reason: Generic protein-binding term with no functional specificity; partners are from high-throughput Y2H/AP-MS, not from the splicing literature.
|
|
GO:0000776
kinetochore
|
IDA
PMID:20813266 The protein composition of mitotic chromosomes determined us... |
MARK AS OVER ANNOTATED |
Summary: Source of the disputed kinetochore call (geneontology/go-annotation#6450). PMID:20813266 is a multi-classifier proteomic screen of purified mitotic chromosomes that nicknamed GPATCH11 "CENP-Y" based on a single low-resolution GFP image among ~4,000 candidate proteins. The 2024 patient/mouse study (PMID:39572588) directly examined GPATCH11 localization and reports diffuse nucleoplasm plus centrosome, with no kinetochore signal, and the GPATCH/ spliceosome literature (including the S. pombe ortholog, PMID:42260140) has not confirmed a kinetochore role. The upstream curator who filed go-annotation#6450 explicitly recommends correction. Per CLAUDE.md, prefer MARK_AS_OVER_ANNOTATED rather than silent REMOVE for an experimentally supported call; flag the over-annotation and propose the localization terms that the high-resolution study actually supports.
Reason: Based on a low-resolution image in a high-throughput screen; later dedicated microscopy and patient data show nucleoplasmic + centrosomal localization without kinetochore signal. GO curators have flagged the annotation upstream.
Proposed replacements:
nucleoplasm
centrosome
Supporting Evidence:
PMID:39572588
a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting potential functions in RNA and cilia metabolism
file:human/GPATCH11/GPATCH11-deep-research-falcon.md
GPATCH11 localizes exclusively to centrosomes with no detectable localization at kinetochores or centromeres
|
|
GO:0005654
nucleoplasm
|
IDA
PMID:39572588 GPATCH11 variants cause mis-splicing and early-onset retinal... |
NEW |
Summary: Proposed new annotation based on dedicated localization study showing diffuse nucleoplasmic signal in patient and control fibroblasts and in mouse retina, replacing the disputed kinetochore call.
Reason: High-resolution microscopy in the 2024 study directly supports nucleoplasmic localization for GPATCH11.
Supporting Evidence:
PMID:39572588
a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization
|
|
GO:0005813
centrosome
|
IDA
PMID:39572588 GPATCH11 variants cause mis-splicing and early-onset retinal... |
NEW |
Summary: Proposed new annotation based on dedicated localization study showing centrosomal signal alongside nucleoplasmic signal in patient/control fibroblasts and mouse retina.
Reason: High-resolution microscopy in the 2024 study directly supports centrosomal localization for GPATCH11, consistent with the patient cilium-related phenotype.
Supporting Evidence:
PMID:39572588
a subcellular localization of GPATCH11 characterized by a diffuse presence in the nucleoplasm, as well as centrosomal localization
|
|
GO:0000398
mRNA splicing, via spliceosome
|
ISO
PMID:42260140 GPATCH11 ortholog Sap34 regulates pre-mRNA splicing by inter... |
NEW |
Summary: Proposed new annotation supported by orthologous evidence from the S. pombe Sap34 study, which demonstrates a direct role in pre-mRNA splicing via U2 snRNP and tri-snRNP interactions, and by retinal transcriptomic / proteomic data from the human/mouse GPATCH11 study showing splicing dysregulation upon loss of function.
Reason: Convergent evidence from the S. pombe ortholog (PMID:42260140) and patient/mouse omics (PMID:39572588) supports a core role in pre-mRNA splicing via the spliceosome.
Supporting Evidence:
PMID:42260140
deletion of sap34 leads to a global reduction in splicing efficiency, predominantly associated with increased intron retention
PMID:39572588
Proteomic analysis of mouse retina confirms the roles GPATCH11 plays in RNA processing, splicing, and transcription regulation
file:human/GPATCH11/GPATCH11-deep-research-falcon.md
Transcriptomic analysis of retinas from Gpatch11-mutant mice revealed 299 altered splicing events affecting 178 genes
|
Q: Does human GPATCH11 directly bind and activate a specific human DEAH-box helicase (e.g., DHX15, the human Prp43 ortholog), analogous to Sap34→Prp43 in fission yeast?
Q: Is the centrosomal pool of GPATCH11 mechanistically tied to primary cilium assembly/function, or does it reflect a regulatory role for splicing of cilium-related transcripts?
Q: Which GPATCH11-dependent splicing events drive the photoreceptor and neurological phenotypes seen in the c.328+1G>T patient cohort?
Experiment: Co-IP / cross-linking MS in human cells to map the GPATCH11 interactome against U2 snRNP, tri-snRNP and DHX15, mirroring the Sap34 study in S. pombe.
Experiment: High-resolution immunofluorescence and live-cell imaging of endogenously tagged GPATCH11 across mitotic stages to directly test for any kinetochore pool, settling the open IBA/IDA call.
Experiment: Long-read RNA-seq of GPATCH11-depleted human retinal organoids or patient-derived photoreceptor cultures to define the splicing programs affected by loss of function.
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.
GPATCH11 (G-patch domain-containing protein 11), also known as CENP-Y (Centromeric protein Y) and CCDC75 (Coiled-coil domain-containing protein 75), is a human gene encoding a 264-amino acid protein that belongs to the GPATCH11 family (zanetti2024gpatch11variantscause pages 1-2). The protein is characterized by three main structural domains: a G-patch domain (IPR000467), a coiled-coil domain, and a DUF4187 domain (IPR025239) (zanetti2024gpatch11variantscause pages 1-2, karika2026gpatchproteinsimportant pages 1-2).
GPATCH11 functions primarily as a regulator of RNA metabolism rather than as an enzyme with catalytic activity (zanetti2024gpatch11variantscause pages 1-2, perrault2023gpatch11variantscause pages 1-7). As a member of the G-patch protein family, GPATCH11 is predicted to act as a cofactor for DEAH-box RNA helicases, which are ATP-dependent enzymes involved in RNA remodeling (bohnsack2021regulationofdeahbox pages 1-2, karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4). The G-patch domain, a conserved glycine-rich motif of approximately 50 amino acids, is the defining feature that enables these proteins to bind and stimulate the ATPase activity of DEAH/RHA-box RNA helicases (bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4).
The G-patch domain in GPATCH11 is encoded by exons 3-5 and bridges the helix and loop braces that are critical for helicase interaction (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 3-4). Recent studies of pathogenic mutations have provided functional evidence for the importance of this domain. A recurrent splice-site mutation (c.328+1G>T) specifically removes 14 amino acids (aa 96-109) from the internal portion of the G-patch domain while preserving the flanking coiled-coil and DUF4187 domains, resulting in a shortened but stable protein product (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5). This mutation causes early-onset retinal dystrophy with neurological impairment, demonstrating the functional criticality of the intact G-patch domain (zanetti2024gpatch11variantscause pages 1-2).
The consensus G-patch motif follows the pattern Gx2hhx3Gax2GxGlGx3pxux3sx10-16GhG, featuring seven highly conserved glycine residues, an invariable aromatic amino acid following the second glycine, and three defined hydrophobic patches (bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4). This intrinsically disordered region enables flexible interaction with RNA helicases, functioning as a molecular brace that links dynamic helicase regions while maintaining catalytic flexibility (karika2026gpatchproteinsimportant pages 2-4).
GPATCH11 plays a dual role in pre-mRNA splicing and transcriptional regulation (zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). Transcriptomic analysis of retinas from Gpatch11-mutant mice revealed 299 altered splicing events affecting 178 genes, with predominant changes in skipped exons and mutually exclusive exons (zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11). These splicing alterations primarily impacted genes involved in photoreceptor light responses, RNA regulation, and primary cilia-associated metabolism (zanetti2024gpatch11variantscause pages 1-2).
Additionally, the protein regulates gene expression at the transcriptional level. Mutant mouse retinas showed 160 differentially expressed genes enriched in pathways related to visual perception, photoreceptor development, and response to light stimuli (zanetti2024gpatch11variantscause pages 8-9). The dual function in both splicing and transcription is consistent with other GPATCH family members such as SON and ZGPAT (zanetti2024gpatch11variantscause pages 11-12).
Immunoprecipitation-mass spectrometry studies identified approximately 50 proteins that associate with GPATCH11, with about 23% being RNA-binding proteins involved in RNA metabolism (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). Key interaction partners include:
Splicing factors: DDX23 (a DEAH-box RNA helicase), PRPF31 (U4/U6-specific protein), PPIL1 (peptidylprolyl isomerase), CHERP (G-patch domain-containing splicing regulator), SF3B2, SF3B3, SF3B4 (U2 snRNP components), PRPF3 (U4/U6), PRPF6, DDX23, TXNL4 (U5), PRPF40A, RBM39 (Complex A), DHX16 (1st Step), and LSM14A (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12).
Transcription regulators: IRF2BPL, ZFP287, FGF2, SAP18 (transcriptional repression enhancer) (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12).
Stress response proteins: NMNAT1 (involved in neuroprotection against light-induced damage), proteins associated with nuclear stress response (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13).
Centrosomal/cytoskeletal proteins: Rootletin/CROCC (centrosome linker protein) (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 11-12).
Notably, analysis of small nuclear RNAs (snRNAs) in patient fibroblasts carrying the G-patch domain mutation showed comparable abundance of U1, U2, U4, U5, and U6 snRNAs compared to controls, suggesting that GPATCH11 does not directly regulate snRNA levels but rather modulates spliceosome activity through protein-protein interactions (zanetti2024gpatch11variantscause pages 6-7).
GPATCH11 exhibits a unique dual subcellular localization pattern characterized by presence in both nuclear and centrosomal compartments (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5).
Nuclear localization: Confocal microscopy of human fibroblasts fixed with methanol and paraformaldehyde revealed a diffuse presence of GPATCH11 throughout the nucleoplasm (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 5-6). The protein shows proximity to SC-35-positive nuclear speckles and H3K9me3-marked heterochromatin regions, a distribution pattern characteristic of spliceosome components and centrosome-associated spliceosome proteins (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). This nucleo-centrosomal localization aligns with recent findings describing centrosome-associated spliceosome components as crucial players in ciliogenesis and tissue specification (zanetti2024gpatch11variantscause pages 12-13).
Centrosomal localization: GPATCH11 localizes to the centrosome linker region, basal body, and centrioles (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 4-5). Stimulated-emission-depletion (STED) microscopy revealed specific association with Rootletin-marked linker fibers in the centrosome linker region (zanetti2024gpatch11variantscause pages 3-4). Notably, centrosomal staining was reduced in paraformaldehyde-fixed cells compared to methanol-fixed cells, suggesting the fixation method affects epitope accessibility (zanetti2024gpatch11variantscause pages 3-4).
Not centromeric/kinetochore: Despite the historical alias "CENP-Y" (Centromeric protein Y), which was assigned based on its identification in mitotic chromosome preparations (ohta2010theproteincomposition pages 1-2), detailed immunostaining analysis at various mitotic stages demonstrated that GPATCH11 localizes exclusively to centrosomes with no detectable localization at kinetochores or centromeres (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5). This finding clarifies that the CENP-Y designation is a misnomer, and the protein does not participate in kinetochore or centromere functions.
In mouse retinal tissue, GPATCH11 is expressed in all retinal nuclear layers, including the outer nuclear layer (photoreceptor nuclei), inner nuclear layer, and ganglion cell layer (zanetti2024gpatch11variantscause pages 7-8). Interestingly, in photoreceptor nuclei, the protein displays a perinuclear distribution pattern rather than the nucleoplasmic localization observed in other retinal cells, likely reflecting the unique inverted nuclear architecture characteristic of nocturnal mammalian photoreceptors (zanetti2024gpatch11variantscause pages 8-9).
GPATCH11 is also strongly expressed in the hippocampus and throughout the brain, consistent with its role in neurological function and the memory deficits observed in mutant mouse models (zanetti2024gpatch11variantscause pages 7-8, zanetti2024gpatch11variantscause pages 8-9).
Functional studies using CRISPR-Cas9-generated deletions demonstrated that neither the G-patch domain nor the coiled-coil (CCDC) domain is solely responsible for the nucleo-centrosomal localization pattern. Cells expressing GPATCH11 lacking the CCDC domain (exon 3 deletion) maintained normal centrosomal and nucleoplasmic distribution, and patient fibroblasts with the G-patch domain alteration (c.328+1G>T) similarly showed unchanged subcellular localization (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5). These findings suggest that multiple regions of the protein contribute to its targeting and that the overall protein architecture, rather than individual domains, determines subcellular distribution.
GPATCH11 is centrally involved in regulating pre-mRNA splicing through its association with the spliceosome machinery (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11). As a G-patch protein, it likely facilitates the dynamic transitions required for spliceosome activation, catalysis, and disassembly by modulating DEAH-box RNA helicase activity (bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4). The spliceosome undergoes extensive structural and compositional rearrangements during each splicing cycle, and RNA helicases with their G-patch cofactors are central to these remodeling events (karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4).
Proteomic analysis revealed that GPATCH11-associated proteins include multiple spliceosomal components from different snRNP complexes and spliceosomal stages, supporting its role as a spliceosome-associated regulatory factor (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). Notably, several of the dysregulated spliceosomal proteins identified in GPATCH11-deficient retinas are encoded by genes that, when mutated, cause retinal dystrophies (retina-specific spliceosomopathies), including PRPF31, PRPF6, PRPF3, and PRPF4 (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12).
Beyond splicing, GPATCH11 participates in broader gene expression control (zanetti2024gpatch11variantscause pages 10-11, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). The protein associates with transcription factors and chromatin-modifying complexes, and its dysfunction leads to altered gene expression patterns. In mutant mouse retinas, 160 genes showed differential expression, with Gene Ontology enrichment indicating dysregulation of photoreceptor development, visual perception, and response to light stimuli (zanetti2024gpatch11variantscause pages 8-9).
The reduction in mRNA abundance observed for many genes could result from multiple mechanisms: direct effects on transcription, splicing aberrations leading to nonsense-mediated mRNA decay of transcripts with premature termination codons, or indirect consequences of splicing dysregulation (zanetti2024gpatch11variantscause pages 11-12). However, for certain genes such as ARR3 (cone arrestin), splicing alterations occurred without changes in reading frame, suggesting GPATCH11 influences both splicing fidelity and transcriptional output independently (zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11).
GPATCH11 plays a critical role in photoreceptor cell function and maintenance (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11). Transcriptomic and proteomic analyses from Gpatch11-mutant mouse retinas revealed enrichment of dysregulated genes and proteins involved in:
Phototransduction cascade: Visual perception pathways including genes encoding proteins essential for light response (CNGA1, GNAT1, RGS9, RS1, TULP1, UNC119, ARR3, RHO, SLC24A1, PRCD, PROM1, RAX, SLC25A25, TMEM237) (zanetti2024gpatch11variantscause pages 10-11).
Photoreceptor-specific metabolism: Primary cilium assembly and non-motile cilium components critical for photoreceptor outer segment structure and function (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 8-9).
Synaptic function: Proteins involved in neurotransmission, synapse architecture, and synaptic plasticity (ATP6V1B2, UNC13B, SLC17A7, RIMS2, DMD, MPDZ, PTPRT, HOMER3, CPEB4, CABP4) (zanetti2024gpatch11variantscause pages 10-11, zanetti2024gpatch11variantscause pages 12-13).
Longitudinal studies in Gpatch11Δ5/Δ5 mice demonstrated that the retina develops normally and responds appropriately to light at eye-opening (postnatal day 15), but undergoes progressive degeneration with light exposure (zanetti2024gpatch11variantscause pages 6-7, zanetti2024gpatch11variantscause pages 7-8). By 3 months of age, approximately half of photoreceptor nuclei were lost, and by 6 months, electroretinogram responses were flat with near-complete photoreceptor loss (zanetti2024gpatch11variantscause pages 7-8). This pattern suggests GPATCH11 is essential for photoreceptor maintenance and function rather than initial development, consistent with many genes associated with Leber congenital amaurosis and retinitis pigmentosa (zanetti2024gpatch11variantscause pages 11-12).
The centrosomal localization of GPATCH11 and the enrichment of cilium-associated genes among dysregulated transcripts suggest involvement in ciliary biology (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 12-13). The centrosome serves as the basal body for primary cilia, and several centrosome-associated spliceosome components have been reported as regulators of ciliogenesis (zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 12-13).
However, functional studies examining primary cilia in patient fibroblasts (carrying the c.328+1G>T G-patch domain mutation) and in hTERT-RPE1 cells lacking the CCDC domain showed no significant differences in the abundance of ciliated cells or mean axonemal length compared to controls (zanetti2024gpatch11variantscause pages 5-6). Similarly, Sonic Hedgehog (SHH) pathway signaling, which is closely linked to primary cilia function, remained intact in patient fibroblasts as evidenced by normal expression of PTCH1, GLI1, and GLI2 in response to smoothened agonist treatment (zanetti2024gpatch11variantscause pages 5-6).
These findings suggest that while GPATCH11 localizes to centrosomal structures and its dysfunction affects cilium-related gene expression in specialized tissues like the retina (where photoreceptor connecting cilia are critical), it may not be required for primary cilia formation or function in all cell types (zanetti2024gpatch11variantscause pages 12-13). The impact on ciliary biology appears to be tissue-specific and context-dependent.
Proteomic analysis identified numerous GPATCH11-associated proteins involved in synaptogenesis, synapse architecture, neurotransmission, and synaptic plasticity (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 12-13). This is consistent with the neurological phenotypes observed in both human patients and mouse models, including intellectual disability, developmental delays, seizures, and memory deficits (zanetti2024gpatch11variantscause pages 1-2, perrault2023gpatch11variantscause pages 1-7, zanetti2024gpatch11variantscause pages 8-9).
Behavioral testing of 1-month-old Gpatch11Δ5/Δ5 mice revealed defects in episodic memory (novel object recognition test) and associative memory (contextual fear conditioning), while spatial memory and anxiety-like behavior remained normal (zanetti2024gpatch11variantscause pages 8-9). The strong expression of GPATCH11 in the hippocampus, a brain region crucial for memory consolidation, supports its role in hippocampal functions (zanetti2024gpatch11variantscause pages 7-8, zanetti2024gpatch11variantscause pages 8-9).
GPATCH11 interacts with proteins involved in cellular stress responses and neuroprotection (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). Notably, NMNAT1, a protein that plays crucial roles in neuroprotection against light-induced damage and is itself a causative gene for nonsyndromic and syndromic Leber congenital amaurosis, was identified as a GPATCH11-interacting protein (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). This suggests GPATCH11 may participate in regulating the expression of genes with neuroprotective functions, which could explain why photoreceptor degeneration in the mouse model progresses with light exposure (zanetti2024gpatch11variantscause pages 11-12).
Additional stress-response proteins and nuclear stress-response factors were identified among GPATCH11 partners, indicating potential roles beyond splicing in maintaining cellular homeostasis under stress conditions (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 12-13).
The centrosomal localization and identification of protein partners involved in cytokinesis and cell division suggest GPATCH11 may play roles in mitotic processes (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). Interestingly, male Gpatch11Δ5/Δ5 mice were completely infertile with smaller, empty testes, while female fertility remained normal (zanetti2024gpatch11variantscause pages 6-7). This severe male-specific phenotype affecting gonadal development has not been reported in human male patients to date, but warrants further clinical investigation (zanetti2024gpatch11variantscause pages 11-12).
The most comprehensive evidence for GPATCH11 function comes from a landmark study published in Nature Communications in November 2024 by Zanetti, Perrault, and colleagues (zanetti2024gpatch11variantscause pages 1-2, perrault2023gpatch11variantscause pages 1-7). This study identified biallelic GPATCH11 variants in 12 affected individuals from 6 unrelated families with diverse geographic origins (Tunisia, Algeria, Morocco, Portugal, Israel) presenting with early-onset retinal dystrophy, neurological impairment, and skeletal abnormalities.
Four distinct pathogenic variants were identified:
c.328+1G>T (found in homozygosity in Families 1, 3, and 6; in compound heterozygosity in Family 2): This splice-site mutation causes in-frame skipping of exon 4, resulting in deletion of 14 amino acids (p.Gly97_Thr110del) from the central portion of the G-patch domain (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 3-4).
c.454C>T (p.Arg152*): A nonsense mutation found in compound heterozygosity with c.328+1G>T in Family 2, predicted to trigger nonsense-mediated mRNA decay (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 3-4).
c.449+1G>C: A splice-site mutation found in homozygosity in Family 4, causing both partial and complete retention of intron 5 (zanetti2024gpatch11variantscause pages 3-4).
c.393C>G (p.Tyr131*): A nonsense mutation found in homozygosity in Family 5, predicted to result in loss of GPATCH11 protein (zanetti2024gpatch11variantscause pages 1-2).
Haplotype reconstruction identified a shared 1.27 Mb haplotype encompassing the c.328+1G>T variant in families from the Maghreb region (Tunisia, Algeria, Morocco), supporting an ancient founder effect (zanetti2024gpatch11variantscause pages 3-4).
A CRISPR-Cas9-generated mouse model with homozygous deletion of exon 5 (corresponding to human exon 4), designated Gpatch11Δ5/Δ5, faithfully recapitulated key aspects of the human phenotype (zanetti2024gpatch11variantscause pages 6-7). These mice were viable and developed normally but exhibited:
Progressive retinal degeneration: Normal retinal development and ERG responses at eye-opening (postnatal day 15), followed by progressive decline in both rod and cone function, with approximately 50% photoreceptor loss by 3 months and near-complete loss by 6 months (zanetti2024gpatch11variantscause pages 6-7, zanetti2024gpatch11variantscause pages 7-8).
Memory impairment: Defects in episodic memory (novel object recognition) and associative memory (contextual fear conditioning) at 1 month of age (zanetti2024gpatch11variantscause pages 8-9).
Male infertility: Complete infertility in males with smaller, empty testes, while females retained normal fertility (zanetti2024gpatch11variantscause pages 6-7).
Western blot analysis confirmed expression of a shortened GPATCH11 protein (36 kDa vs. 37 kDa wild-type) in mutant retinas, with accumulation of the mutant protein to levels exceeding wild-type despite similar mRNA abundance (zanetti2024gpatch11variantscause pages 6-7, zanetti2024gpatch11variantscause pages 8-9). This accumulation suggests altered protein degradation, potentially due to loss of post-translational modification sites or changes in protein stability (zanetti2024gpatch11variantscause pages 8-9).
RNA-sequencing of retinas from 15-day-old Gpatch11Δ5/Δ5 mice versus wild-type littermates revealed extensive transcriptomic dysregulation (zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11):
160 differentially expressed genes (DEGs) with enrichment for photoreceptor-related pathways, non-motile cilium components, and light response genes (zanetti2024gpatch11variantscause pages 8-9).
299 splicing events in 178 genes (differentially spliced genes, DSGs), predominantly involving skipped exons and mutually exclusive exons (zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 10-11).
Only 12 genes showed both differential expression and altered splicing, suggesting that splicing changes and transcriptional dysregulation largely represent independent effects of GPATCH11 dysfunction (zanetti2024gpatch11variantscause pages 10-11).
Gene Ontology analysis identified dysregulated pathways including visual perception, photoreceptor cell development, response to light stimulus, cilium assembly, protein homeostasis, mitochondrial function, chromatin binding, and regulation of RNA splicing (zanetti2024gpatch11variantscause pages 10-11).
Mass spectrometry analysis of total retinal lysates from 21-day-old mice identified 150 proteins with altered abundance (63 decreased, 87 increased) in Gpatch11Δ5/Δ5 retinas (zanetti2024gpatch11variantscause pages 9-10). Downregulated proteins included those encoded by genes associated with retinal diseases (TULP1 linked to Leber congenital amaurosis, CABP4 linked to cone-rod synaptic disorder, ARR3/cone arrestin) as well as RNA-binding proteins and spliceosomal components (zanetti2024gpatch11variantscause pages 9-10).
Upregulated proteins were enriched for RNA-binding proteins, including multiple spliceosomal components (PRPF39, CHERP, SF3B2, SF3B3, SF3B4, PRPF3, DDX23, PRPF6, TXNL4, PRPF40A, RBM39, DHX16, SRFS6, LSM14A), consistent with a compensatory response or accumulation due to dysregulated RNA metabolism (zanetti2024gpatch11variantscause pages 9-10).
Immunoprecipitation-mass spectrometry using GPATCH11 antibody identified approximately 50 protein partners in wild-type and mutant retinas, with 30 proteins common to both, 16 uniquely enriched in mutant, and 4 unique to wild-type (zanetti2024gpatch11variantscause pages 9-10). Approximately 23% of these interactors are involved in RNA metabolism, highlighting GPATCH11's central role in RNA processing networks (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12).
Recent reviews of G-patch proteins provide broader context for understanding GPATCH11 function (bohnsack2021regulationofdeahbox pages 1-2, karika2026gpatchproteinsimportant pages 1-2, bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4). The G-patch domain functions as a flexible molecular brace that binds to DEAH-box RNA helicases and enhances their ATPase activity by inducing subtle conformational changes that facilitate ATP binding and hydrolysis (karika2026gpatchproteinsimportant pages 2-4). The domain links dynamic regions of RNA helicases while maintaining the flexibility required for efficient catalysis (karika2026gpatchproteinsimportant pages 2-4).
G-patch proteins are conserved throughout eukaryotes but absent from bacteria and archaea, suggesting co-evolution with the increasing complexity of eukaryotic RNA processing and ribosome biogenesis (karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4). In humans, more than 20 G-patch proteins have been identified, with functions extending beyond splicing to include ribosome biogenesis, RNA export, rRNA maturation, snoRNA maturation, telomere maintenance, and innate immune responses (bohnsack2021regulationofdeahbox pages 1-2, karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4).
Dysregulation or mutation of G-patch proteins has been linked to various diseases, including aberrant mRNA maturation, altered splicing patterns, impaired ribosome assembly, genomic instability, and cancer progression (karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4). Prior to the GPATCH11 studies, only RBM10 and SON among G-patch family members had been associated with severe multisystem developmental syndromes (zanetti2024gpatch11variantscause pages 1-2, perrault2023gpatch11variantscause pages 1-7).
| Category | Specific Function/Feature | Evidence Type | Key Findings |
|---|---|---|---|
| Protein Structure/Domains | G-patch domain | Domain/family review; patient mutation analysis | GPATCH11 is a human G-patch protein with a conserved glycine-rich G-patch motif, a hallmark domain that in the broader family typically regulates DEAH/RHA RNA helicases. In GPATCH11, a recurrent pathogenic splice variant removes 14 aa from the G-patch region, supporting functional importance of this domain (bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4, zanetti2024gpatch11variantscause pages 4-5). |
| Protein Structure/Domains | Coiled-coil/CCDC region | Sequence/domain annotation; CRISPR deletion functional study | GPATCH11 is also known as CCDC75, reflecting a coiled-coil domain. Deletion of the CCDC-encoding region in hTERT-RPE1 cells did not alter nucleo-centrosomal localization, suggesting the coiled-coil region is not solely responsible for targeting to those compartments (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 4-5). |
| Protein Structure/Domains | DUF4187 and overall domain architecture | Domain annotation; human G-patch family review | The UniProt-linked protein architecture includes G-patch, coiled-coil, and DUF4187-related features; reviews emphasize that human G-patch proteins commonly combine the G-patch with additional RNA-binding or interaction modules, consistent with multifunctional RNA-metabolism roles (zanetti2024gpatch11variantscause pages 1-2, karika2026gpatchproteinsimportant pages 1-2, karika2026gpatchproteinsimportant pages 2-4). |
| Molecular Function | RNA metabolism regulator | Human disease paper; family review | Zanetti et al. describe GPATCH11 as a lesser-known regulator of RNA metabolism. Their genetic, transcriptomic, and proteomic data support roles in RNA processing, splicing, and transcriptional regulation rather than enzymatic catalysis (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 10-11, zanetti2024gpatch11variantscause pages 12-13). |
| Molecular Function | Putative RNA helicase cofactor via G-patch domain | Mechanistic reviews; inference from family biology | Reviews of G-patch proteins state that the core function of the G-patch motif is to bind and stimulate DEAH/RHA-box RNA helicases, enhancing ATPase/helicase activity and RNA remodeling. Although GPATCH11’s direct helicase partner remains unconfirmed, its function is plausibly analogous by family logic (bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4). |
| Molecular Function | Pre-mRNA splicing regulator | Mouse retina transcriptomics; proteomics; discussion synthesis | Mutant Gpatch11 mouse retina showed 299 altered splicing events in 178 genes, and GPATCH11-associated proteins included spliceosomal/RNA-metabolism factors, strongly supporting a role in splicing regulation (zanetti2024gpatch11variantscause pages 8-9, zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). |
| Molecular Function | Transcriptional regulation | Proteomics and protein interaction analysis | GPATCH11-associated proteins included factors involved in transcription regulation, and the authors argue GPATCH11 likely influences both splicing and transcription, analogous to other GPATCH family members with multifunctional nuclear roles (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). |
| Subcellular Localization | Nucleoplasmic localization | Immunocytochemistry/confocal microscopy in human fibroblasts | GPATCH11 shows diffuse nucleoplasmic distribution in control fibroblasts and is proximal to SC-35-positive speckles and H3K9me3-marked heterochromatin, consistent with nuclear RNA-processing machinery (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 11-12). |
| Subcellular Localization | Centrosomal localization | Confocal/STED microscopy | GPATCH11 localizes to the centrosome linker region and basal-body-associated structures, including association with Rootletin/CROCC-marked linker fibers, supporting a nucleo-centrosomal distribution (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 11-12). |
| Subcellular Localization | Not centromeric/kinetochore despite alias CENP-Y | Mitotic-stage imaging in human cells | Despite the historical alias “CENP-Y,” Zanetti et al. found GPATCH11 exclusively at centrosomes during mitosis, with no detectable localization at centromeres or kinetochores in their assays (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5). |
| Subcellular Localization | Retinal and brain nuclear expression | Mouse immunohistochemistry | In mouse tissue, GPATCH11 protein was detected in all retinal nuclear layers and strongly in the hippocampus and broader brain, supporting roles in retinal and neural physiology (zanetti2024gpatch11variantscause pages 7-8). |
| Biological Processes/Pathways | Alternative splicing and spliceosome-linked regulation | Transcriptomics; family reviews | GPATCH11 perturbation alters splicing broadly, while G-patch protein reviews place such proteins centrally in spliceosome remodeling through RNA helicase regulation. Together these support GPATCH11 as a spliceosome-associated regulatory factor (zanetti2024gpatch11variantscause pages 8-9, bohnsack2021regulationofdeahbox pages 2-4, karika2026gpatchproteinsimportant pages 2-4). |
| Biological Processes/Pathways | Gene expression control in photoreceptors | Differential expression analysis in mutant mouse retina | Mutant retina showed 160 differentially expressed genes enriched for visual perception, photoreceptor development, response to light stimulus, and non-motile cilium categories, indicating GPATCH11 is important for retinal gene-expression homeostasis (zanetti2024gpatch11variantscause pages 8-9). |
| Biological Processes/Pathways | Ciliary/centrosomal biology | Localization studies; pathway enrichment | Centrosomal/basal body localization plus retinal transcriptomic enrichment for cilium-associated genes suggests participation in cilia-related biology, although direct ciliogenesis defects were not seen in fibroblasts (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 5-6, zanetti2024gpatch11variantscause pages 12-13). |
| Biological Processes/Pathways | Synaptic plasticity and neuronal function | Retina proteomics and interaction proteomics | Proteomic analyses suggested additional roles in synaptic plasticity, synaptogenesis, neurotransmission, and neuronal maintenance, potentially explaining memory phenotypes in the mouse model (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 12-13). |
| Biological Processes/Pathways | Stress-response and neuroprotection-linked pathways | Interaction proteomics; discussion | GPATCH11-associated proteins included stress-response and nuclear homeostasis factors, and the paper discusses possible links to neuroprotective pathways relevant to retinal degeneration (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12, zanetti2024gpatch11variantscause pages 12-13). |
| Protein Partners | RNA/splicing factors | Immunoprecipitation-mass spectrometry | GPATCH11-associated proteins included DDX23, PRPF31, PPIL1 and other RNA-metabolism factors; about 23% of interactors were involved in RNA metabolism, reinforcing a splicing/transcription role (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). |
| Protein Partners | Centrosomal linker factor Rootletin/CROCC | Microscopy colocalization | STED/confocal imaging placed GPATCH11 with Rootletin in the centrosome linker region, suggesting functional coupling to centrosomal organization (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 11-12). |
| Protein Partners | Transcription/stress-associated proteins | Immunoprecipitation-mass spectrometry | GPATCH11 pull-downs recovered proteins such as IRF2BPL, ZFP287, FGF2, SAP18, and NMNAT1, linking GPATCH11 to transcriptional control, nuclear repression, and stress-response/neuroprotection networks (zanetti2024gpatch11variantscause pages 9-10, zanetti2024gpatch11variantscause pages 11-12). |
| Disease Association | Autosomal recessive syndromic retinal dystrophy with neurological impairment | Human genetics; clinical cohort | Biallelic GPATCH11 variants were identified in 12 affected individuals from 6 families, causing early-onset retinal dystrophy with intellectual/neurological impairment and craniofacial/skeletal features (zanetti2024gpatch11variantscause pages 1-2, zanetti2024gpatch11variantscause pages 2-3, perrault2023gpatch11variantscause pages 1-7). |
| Disease Association | Mutation classes and molecular consequences | RNA/protein analysis in patient cells | Reported pathogenic alleles included splice-site and nonsense variants; c.328+1G>T caused in-frame exon 4 skipping and a shorter protein lacking part of the G-patch domain, while other variants caused intron retention or likely nonsense-mediated decay (zanetti2024gpatch11variantscause pages 3-4, zanetti2024gpatch11variantscause pages 4-5). |
| Disease Association | Mouse model recapitulates core phenotype | CRISPR mouse model; ERG/behavioral assays | Gpatch11Δ5/Δ5 mice were viable but developed progressive retinal degeneration, memory deficits, and male infertility, supporting a causal role for GPATCH11 dysfunction and highlighting tissue-specific physiological importance (zanetti2024gpatch11variantscause pages 6-7, zanetti2024gpatch11variantscause pages 7-8). |
Table: This table summarizes current evidence on GPATCH11 structure, function, localization, pathways, partners, and disease relevance. It is useful as a compact evidence map grounded in the key GPATCH11 disease study and authoritative G-patch protein reviews.
GPATCH11 is a multifunctional regulator of RNA metabolism that acts primarily through its G-patch domain to modulate pre-mRNA splicing and gene transcription. The protein exhibits unique nucleo-centrosomal localization, functioning both as a spliceosome-associated component in the nucleus and as a centrosomal protein with potential roles in ciliary biology and cell division.
Biallelic loss-of-function mutations in GPATCH11 cause a syndromic disorder characterized by early-onset retinal dystrophy, neurological impairment (intellectual disability, developmental delays, seizures, memory deficits), and dysmorphic features. The disease mechanism involves widespread dysregulation of RNA splicing and gene expression, particularly affecting photoreceptor-specific genes, synaptic function genes, and ciliary metabolism pathways.
The recent identification of GPATCH11 as a disease gene (2023-2024) has significantly expanded our understanding of spliceosomopathies and their intersection with ciliopathies. The dual nucleo-centrosomal localization of GPATCH11 exemplifies the emerging concept of centrosome-associated spliceosome components that link RNA processing to cellular specialization and ciliogenesis.
Future research directions include identifying the specific DEAH-box RNA helicase(s) regulated by GPATCH11, elucidating the molecular basis for tissue-specific phenotypes, investigating the role of protein accumulation in disease pathogenesis, and determining whether male fertility should be assessed in affected individuals. The extensive characterization of GPATCH11 through human genetics, mouse models, and multi-omics approaches provides a strong foundation for understanding this critical RNA metabolism regulator and developing potential therapeutic strategies for affected individuals.
References
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(zanetti2024gpatch11variantscause pages 10-11): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
(zanetti2024gpatch11variantscause pages 9-10): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
(zanetti2024gpatch11variantscause pages 6-7): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
(zanetti2024gpatch11variantscause pages 5-6): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
(ohta2010theproteincomposition pages 1-2): Shinya Ohta, Jimi-Carlo Bukowski-Wills, Luis Sanchez-Pulido, Flavia de Lima Alves, Laura Wood, Zhuo A. Chen, Melpi Platani, Lutz Fischer, Damien F. Hudson, Chris P. Ponting, Tatsuo Fukagawa, William C. Earnshaw, and Juri Rappsilber. The protein composition of mitotic chromosomes determined using multiclassifier combinatorial proteomics. Cell, 142:810-821, Sep 2010. URL: https://doi.org/10.1016/j.cell.2010.07.047, doi:10.1016/j.cell.2010.07.047. This article has 377 citations and is from a highest quality peer-reviewed journal.
(zanetti2024gpatch11variantscause pages 7-8): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
(zanetti2024gpatch11variantscause pages 2-3): Andrea Zanetti, Gwendal Dujardin, Lucas Fares-Taie, Jeanne Amiel, Jérôme E. Roger, Isabelle Audo, Matthieu P. Robert, Pierre David, Vincent Jung, Nicolas Goudin, Ida Chiara Guerrera, Stéphanie Moriceau, Danielle Amana, Nurit Assia Batzir, Anat Bachar-Zipori, Lina Basel Salmon, Nathalie Boddaert, Sylvain Briault, Ange-Line Bruel, Christine Costet-Fighiera, Luisa Coutinho Santos, Cyril Gitiaux, Karolina Kaminska, Paul Kuentz, Naama Orenstein, Nicole Philip-Sarles, Morgane Plutino, Mathieu Quinodoz, Cristina Santos, Sabine Sigaudy, Mariana Soeiro e Sá, Efrat Sofrin, Ana Berta Sousa, Rui Sousa-Luis, Christel Thauvin-Robinet, Erwin L. van Dijk, Khaoula Zaafrane-Khachnaoui, Dinah Zur, Josseline Kaplan, Carlo Rivolta, Jean-Michel Rozet, and Isabelle Perrault. Gpatch11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-54549-8, doi:10.1038/s41467-024-54549-8. This article has 6 citations and is from a highest quality peer-reviewed journal.
UniProt: Q8N954 (GPT11_HUMAN). Also called CCDC75 and "centromere protein Y / CENP-Y"
(the latter from the 2010 Ohta et al. proteomic screen, not the protein's established role).
HGNC:26768. Member of the GPATCH family of G-patch-domain RNA/spliceosome regulators.
The annotation review is prompted by geneontology/go-annotation#6450, which flags the
IBA is_active_in kinetochore annotation (propagated from the 2010 IDA) as likely incorrect.
The upstream curator notes the 2010 image is low-resolution and that the 2024 Nat Commun
patient study explicitly does not observe kinetochore localization, instead reporting
diffuse nucleoplasmic and centrosomal localization plus a clear pre-mRNA splicing role.
A new (2026) Sci Rep paper on the S. pombe ortholog Sap34 corroborates the splicing role.
Pre-mRNA splicing regulator via the G-patch / DEAH-helicase axis. GPATCH11 belongs
to the GPATCH family, whose hallmark glycine-rich G-patch motif activates DEAH-box RNA
helicases on spliceosomal/RNP substrates PMID:39572588. The fission yeast ortholog Sap34 binds U2
snRNP and U4/U6·U5 tri-snRNP components and activates Prp43 via its G-patch domain;
sap34Δ causes a global splicing defect with increased intron retention
[PMID:42260140 "Sap34 forms a complex with components of the U2 small nuclear
ribonucleoprotein (snRNP) and the U4/U6 × U5 tri-snRNP", "deletion of sap34 leads to a
global reduction in splicing efficiency, predominantly associated with increased intron
retention"]. Human GPATCH11 patient retina shows dysregulated splicing in proteomics
and transcriptomics PMID:39572588.
Subcellular localization: nucleoplasm + centrosome. The 2024 patient study reports
"a diffuse presence in the nucleoplasm, as well as centrosomal localization, suggesting
potential functions in RNA and cilia metabolism" PMID:39572588. No kinetochore signal
is reported. This is consistent with the gene's GPATCH/spliceosome identity.
Disease association. Biallelic loss-of-function variants (recurrent c.328+1G>T splice
variant that removes the G-patch domain) cause a syndrome of early-onset retinal
dystrophy with neurological impairment and skeletal abnormalities
PMID:39572588. OMIM #621183.
The original IDA (PMID:20813266, Ohta et al. 2010) is part of the MCCP large-scale
mitotic chromosome proteomics screen that "identified approximately 4000 polypeptides in
highly purified chromosomes" and confirmed only a subset by GFP tagging. GPATCH11 was named
"CENP-Y" in that paper as a predicted centromere-associated protein based on the screen.
The upstream curator (go-annotation#6450) explicitly states the image supporting the
kinetochore call is "quite low resolution" and that subsequent high-resolution localization
work in the 2024 patient study reports nucleoplasm + centrosome with no kinetochore signal.
CLAUDE.md cautions against overruling experimental IDA from incomplete evidence, but here:
- the GO curator who maintains GO-annotation is themselves recommending removal,
- the 2010 IDA came from a low-resolution screening assay whose authors flagged ~97 of
4,000 hits as "uncharacterized" candidates needing follow-up,
- the 2024 paper directly contradicts the localization with better microscopy in
multiple cell types and a mouse model,
- the centromere-association nickname "CENP-Y" has not been adopted in any downstream
functional literature.
Action: MARK_AS_OVER_ANNOTATED for both the IDA and the IBA kinetochore terms, with
proposed replacement terms GO:0005654 nucleoplasm and GO:0005813 centrosome. Using
MARK_AS_OVER_ANNOTATED rather than REMOVE because the 2010 proteomic evidence is
real (the protein was detected in purified mitotic chromosome fractions) but does not
support a specific kinetochore role; per the CLAUDE.md spirit, we flag rather than
silently delete an experimental annotation while citing the contradicting evidence.
GO:0003676 nucleic acid binding (IEA from InterPro G-patch IPR000467) — supported in
spirit; the G-patch motif is an RNA-binding/helicase-cofactor module. Accept as a
general molecular function; propose a more specific MF capturing the G-patch role
(GO:0003724 RNA helicase activity would be wrong — GPATCH11 is not a helicase; better:
the regulator role via Prp43 binding, GO:0008386 → not applicable). Keep as is; flag
pre-mRNA binding (GO:0036002) as a more informative successor candidate.
GO:0005515 protein binding (IPI from PMID:25416956 / IntAct, partners O00560 SDCBP and
O60242 ADGRB3) — these are Y2H/AP-MS partners with no clear functional relevance to
splicing or cilia. Mark as KEEP_AS_NON_CORE because the binding events themselves are
empirically supported but "protein binding" is uninformative per project guidance.
Pre-mRNA splicing regulator within the spliceosomal U2/tri-snRNP environment, via
G-patch-dependent activation of DEAH helicase Prp43 (paralog: GPATCH1/2). Supported by
PMID:42260140 (Sap34 ortholog) and PMID:39572588 (human/mouse phenotype + proteomics).
Nucleoplasmic + centrosomal localization, consistent with roles in RNA metabolism
and primary cilia function (PMID:39572588).
GO:0000398 mRNA splicing, via spliceosome (BP) — propose as IBA-promotable when theGO:0005654 nucleoplasm (CC) — IDA-supportable from PMID:39572588.GO:0005813 centrosome (CC) — IDA-supportable from PMID:39572588.GO:0005686 U2 snRNP / GO:0046540 U4/U6 × U5 tri-snRNP (CC) — supported in fissiongeneontology/go-annotation#6450
id: Q8N954
gene_symbol: GPATCH11
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: G patch domain-containing protein 11 (also CCDC75; historically nicknamed
CENP-Y), a member of the GPATCH family of glycine-rich G-patch motif proteins that
cooperate with DEAH-box RNA helicases to remodel ribonucleoprotein complexes during
pre-mRNA splicing. GPATCH11 localizes diffusely in the nucleoplasm with additional
signal at the centrosome and acts as a regulator of pre-mRNA splicing; the
Schizosaccharomyces pombe ortholog Sap34 binds U2 snRNP and U4/U6·U5 tri-snRNP
components and activates the DEAH-box helicase Prp43 via its G-patch domain, and
loss of Sap34 causes a global splicing defect with increased intron retention.
Biallelic loss-of-function variants in human GPATCH11 (notably the recurrent
c.328+1G>T splice variant, which removes the G-patch domain) cause a syndrome of
early-onset retinal dystrophy with neurological impairment and craniofacial/skeletal
features, with mouse and patient-derived data implicating mis-splicing, altered
primary-cilium-associated gene expression, and impaired photoreceptor function.
alternative_products:
- name: '1'
id: Q8N954-1
- name: '2'
id: Q8N954-2
sequence_note: VSP_023505, VSP_023506
existing_annotations:
- term:
id: GO:0000776
label: kinetochore
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: PAINT IBA propagated from the single IDA in PMID:20813266. The upstream
GO curators have flagged this annotation (geneontology/go-annotation#6450) as
incorrect because the only experimental source is a low-resolution image from
a large-scale mitotic-chromosome proteomic screen, and the dedicated 2024
patient/mouse study (PMID:39572588) explicitly reports nucleoplasmic and
centrosomal localization with no kinetochore signal. The S. pombe ortholog
Sap34 (PMID:42260140) is a spliceosome-associated protein interacting with
U2 and tri-snRNP components, not a kinetochore protein. The phylogenetic
propagation should be retracted in step with the IDA.
action: MARK_AS_OVER_ANNOTATED
reason: Propagated by PAINT from a disputed IDA; the IBA inherits the same
over-annotation problem. Functional evidence across human, mouse, and
fission yeast converges on a pre-mRNA splicing role, not a kinetochore role.
proposed_replacement_terms:
- id: GO:0005654
label: nucleoplasm
- id: GO:0005813
label: centrosome
supported_by:
- reference_id: PMID:39572588
supporting_text: a subcellular localization of GPATCH11 characterized by a
diffuse presence in the nucleoplasm, as well as centrosomal localization
- reference_id: PMID:42260140
supporting_text: Sap34 forms a complex with components of the U2 small
nuclear ribonucleoprotein (snRNP) and the U4/U6 × U5 tri-snRNP, which are
required for early spliceosome assembly and activation
- reference_id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
supporting_text: GPATCH11 localizes exclusively to centrosomes with no
detectable localization at kinetochores or centromeres
- term:
id: GO:0003676
label: nucleic acid binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: InterPro-derived IEA from the G-patch domain (IPR000467). The G-patch
motif is a well-established RNA-binding/helicase-cofactor module, so this
annotation is correct in spirit but very general. The patient/mouse study
(PMID:39572588) and the S. pombe ortholog characterization (PMID:42260140)
both implicate GPATCH11/Sap34 in pre-mRNA binding and spliceosome remodeling.
Accept as a non-core, broad MF; more specific successor terms below.
action: KEEP_AS_NON_CORE
reason: Domain-based IEA from G-patch (IPR000467); biologically consistent
with the protein's spliceosomal role but not informative on its own. The
falcon deep-research synthesis reinforces the family-level interpretation
that the G-patch motif acts as a DEAH/RHA-box RNA-helicase cofactor rather
than a catalytic enzyme, i.e. the nucleic-acid-binding role is exercised in
the context of helicase regulation during spliceosome remodeling.
additional_reference_ids:
- PMID:39572588
- PMID:42260140
supported_by:
- reference_id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
supporting_text: is predicted to act as a cofactor for DEAH-box RNA helicases,
which are ATP-dependent enzymes involved in RNA remodeling
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
qualifier: enables
review:
summary: IntAct annotation derived from large-scale interactome mapping (Rolland
et al. 2014) with partners SDCBP (O00560) and ADGRB3 (O60242). Per project
guidance, "protein binding" is uninformative and these interactors are not
mechanistically linked to GPATCH11's spliceosomal function. Keep the
interaction-level evidence but mark non-core.
action: KEEP_AS_NON_CORE
reason: Generic protein-binding term with no functional specificity; partners
are from high-throughput Y2H/AP-MS, not from the splicing literature.
- term:
id: GO:0000776
label: kinetochore
evidence_type: IDA
original_reference_id: PMID:20813266
qualifier: located_in
review:
summary: Source of the disputed kinetochore call (geneontology/go-annotation#6450).
PMID:20813266 is a multi-classifier proteomic screen of purified mitotic
chromosomes that nicknamed GPATCH11 "CENP-Y" based on a single low-resolution
GFP image among ~4,000 candidate proteins. The 2024 patient/mouse study
(PMID:39572588) directly examined GPATCH11 localization and reports diffuse
nucleoplasm plus centrosome, with no kinetochore signal, and the GPATCH/
spliceosome literature (including the S. pombe ortholog, PMID:42260140) has
not confirmed a kinetochore role. The upstream curator who filed
go-annotation#6450 explicitly recommends correction. Per CLAUDE.md, prefer
MARK_AS_OVER_ANNOTATED rather than silent REMOVE for an experimentally
supported call; flag the over-annotation and propose the localization terms
that the high-resolution study actually supports.
action: MARK_AS_OVER_ANNOTATED
reason: Based on a low-resolution image in a high-throughput screen; later
dedicated microscopy and patient data show nucleoplasmic + centrosomal
localization without kinetochore signal. GO curators have flagged the
annotation upstream.
proposed_replacement_terms:
- id: GO:0005654
label: nucleoplasm
- id: GO:0005813
label: centrosome
supported_by:
- reference_id: PMID:39572588
supporting_text: a subcellular localization of GPATCH11 characterized by a
diffuse presence in the nucleoplasm, as well as centrosomal localization,
suggesting potential functions in RNA and cilia metabolism
- reference_id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
supporting_text: GPATCH11 localizes exclusively to centrosomes with no
detectable localization at kinetochores or centromeres
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: PMID:39572588
qualifier: located_in
review:
summary: Proposed new annotation based on dedicated localization study showing
diffuse nucleoplasmic signal in patient and control fibroblasts and in mouse
retina, replacing the disputed kinetochore call.
action: NEW
reason: High-resolution microscopy in the 2024 study directly supports
nucleoplasmic localization for GPATCH11.
supported_by:
- reference_id: PMID:39572588
supporting_text: a subcellular localization of GPATCH11 characterized by a
diffuse presence in the nucleoplasm, as well as centrosomal localization
- term:
id: GO:0005813
label: centrosome
evidence_type: IDA
original_reference_id: PMID:39572588
qualifier: located_in
review:
summary: Proposed new annotation based on dedicated localization study showing
centrosomal signal alongside nucleoplasmic signal in patient/control
fibroblasts and mouse retina.
action: NEW
reason: High-resolution microscopy in the 2024 study directly supports
centrosomal localization for GPATCH11, consistent with the patient
cilium-related phenotype.
supported_by:
- reference_id: PMID:39572588
supporting_text: a subcellular localization of GPATCH11 characterized by a
diffuse presence in the nucleoplasm, as well as centrosomal localization
- term:
id: GO:0000398
label: mRNA splicing, via spliceosome
evidence_type: ISO
original_reference_id: PMID:42260140
qualifier: involved_in
review:
summary: Proposed new annotation supported by orthologous evidence from the
S. pombe Sap34 study, which demonstrates a direct role in pre-mRNA splicing
via U2 snRNP and tri-snRNP interactions, and by retinal transcriptomic /
proteomic data from the human/mouse GPATCH11 study showing splicing
dysregulation upon loss of function.
action: NEW
reason: Convergent evidence from the S. pombe ortholog (PMID:42260140) and
patient/mouse omics (PMID:39572588) supports a core role in pre-mRNA
splicing via the spliceosome.
supported_by:
- reference_id: PMID:42260140
supporting_text: deletion of sap34 leads to a global reduction in splicing
efficiency, predominantly associated with increased intron retention
- reference_id: PMID:39572588
supporting_text: Proteomic analysis of mouse retina confirms the roles
GPATCH11 plays in RNA processing, splicing, and transcription regulation
- reference_id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
supporting_text: Transcriptomic analysis of retinas from Gpatch11-mutant mice
revealed 299 altered splicing events affecting 178 genes
core_functions:
- description: Regulator of pre-mRNA splicing acting in or near the early spliceosome
via the G-patch motif, consistent with GPATCH-family function and with the
S. pombe ortholog Sap34, which interacts with U2 snRNP and U4/U6·U5 tri-snRNP
components and activates the DEAH-box helicase Prp43.
supported_by:
- reference_id: PMID:39572588
supporting_text: Proteomic analysis of mouse retina confirms the roles GPATCH11
plays in RNA processing, splicing, and transcription regulation
- reference_id: PMID:42260140
supporting_text: deletion of sap34 leads to a global reduction in splicing
efficiency, predominantly associated with increased intron retention
- reference_id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
supporting_text: GPATCH11 functions primarily as a regulator of RNA metabolism
rather than as an enzyme with catalytic activity
molecular_function:
id: GO:0003676
label: nucleic acid binding
directly_involved_in:
- id: GO:0000398
label: mRNA splicing, via spliceosome
locations:
- id: GO:0005654
label: nucleoplasm
- description: Centrosome-associated component contributing to primary-cilium-related
gene expression programs, as inferred from co-staining and patient-phenotype
transcriptomics; mechanism unresolved.
supported_by:
- reference_id: PMID:39572588
supporting_text: Transcriptomic analysis performed on mouse retina detect
dysregulation in both gene expression and splicing activity, impacting key
processes such as photoreceptor light responses, RNA regulation, and primary
cilia-associated metabolism
molecular_function:
id: GO:0003676
label: nucleic acid binding
locations:
- id: GO:0005813
label: centrosome
proposed_new_terms: []
suggested_questions:
- question: Does human GPATCH11 directly bind and activate a specific human DEAH-box
helicase (e.g., DHX15, the human Prp43 ortholog), analogous to Sap34→Prp43 in
fission yeast?
- question: Is the centrosomal pool of GPATCH11 mechanistically tied to primary
cilium assembly/function, or does it reflect a regulatory role for splicing
of cilium-related transcripts?
- question: Which GPATCH11-dependent splicing events drive the photoreceptor and
neurological phenotypes seen in the c.328+1G>T patient cohort?
suggested_experiments:
- description: Co-IP / cross-linking MS in human cells to map the GPATCH11 interactome
against U2 snRNP, tri-snRNP and DHX15, mirroring the Sap34 study in S. pombe.
- description: High-resolution immunofluorescence and live-cell imaging of endogenously
tagged GPATCH11 across mitotic stages to directly test for any kinetochore
pool, settling the open IBA/IDA call.
- description: Long-read RNA-seq of GPATCH11-depleted human retinal organoids or
patient-derived photoreceptor cultures to define the splicing programs
affected by loss of function.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Standard InterPro→GO electronic-annotation reference; the G-patch
domain (IPR000467) legitimately maps to nucleic acid binding.
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Standard PAINT IBA reference. Here it propagates an erroneous
kinetochore call inherited from PMID:20813266; flagged upstream in
geneontology/go-annotation#6450.
- id: PMID:20813266
title: The protein composition of mitotic chromosomes determined using multiclassifier
combinatorial proteomics.
findings:
- statement: Large-scale proteomic + GFP imaging screen of mitotic chromosomes
that nicknamed GPATCH11 "CENP-Y" and assigned it a kinetochore localization
from a single low-resolution image.
supporting_text: "Indeed, of 34 GFP-tagged predicted chromosomal proteins, 30
were chromosomal, including 13 with centromere-association."
reference_review:
relevance: LOW
correctness: DISPUTED
review_notes: Source of the disputed kinetochore IDA. Genuine proteomics paper
but the per-protein localization assignment for GPATCH11 is based on a
low-resolution image, and a dedicated 2024 study (PMID:39572588) contradicts
the kinetochore call. Upstream GO curators have flagged the derived
annotations in geneontology/go-annotation#6450.
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings:
- statement: High-throughput Y2H interactome reporting GPATCH11 binding partners
SDCBP (O00560) and ADGRB3 (O60242).
supporting_text: GPATCH11 (Q8N954) is included in the IntAct-curated interactions
from this proteome-scale Y2H study.
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Correctly cited for the IntAct IPI evidence, but the listed
partners are not mechanistically informative about GPATCH11's splicing
role.
- id: PMID:39572588
title: GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with
neurological impairment.
findings:
- statement: GPATCH11 localizes diffusely in the nucleoplasm and at the centrosome;
no kinetochore signal reported.
supporting_text: a subcellular localization of GPATCH11 characterized by a
diffuse presence in the nucleoplasm, as well as centrosomal localization
- statement: GPATCH11 loss-of-function causes mis-splicing and dysregulated
photoreceptor / cilia-related gene expression in patient cells and a mouse
model.
supporting_text: Proteomic analysis of mouse retina confirms the roles GPATCH11
plays in RNA processing, splicing, and transcription regulation
- statement: Biallelic loss-of-function variants (recurrent c.328+1G>T removing
the G-patch domain) cause a syndrome of early-onset retinal dystrophy with
neurological impairment and craniofacial/skeletal features.
supporting_text: biallelic GPATCH11 variants are responsible for a syndrome
characterized by early-onset-severe retinal degeneration, neurological
symptoms, and abnormal craniofacial features
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Dedicated patient + mouse study with high-resolution localization
data. Strongest available evidence for the gene's nucleoplasm/centrosome
localization and splicing role; directly contradicts the kinetochore IDA.
- id: PMID:42260140
title: GPATCH11 ortholog Sap34 regulates pre-mRNA splicing by interacting with
early spliceosomal complexes in Schizosaccharomyces pombe.
findings:
- statement: The S. pombe GPATCH11 ortholog Sap34 binds U2 snRNP and U4/U6·U5
tri-snRNP components and activates DEAH-box helicase Prp43 via its G-patch
domain.
supporting_text: Sap34 forms a complex with components of the U2 small nuclear
ribonucleoprotein (snRNP) and the U4/U6 × U5 tri-snRNP, which are required
for early spliceosome assembly and activation
- statement: Loss of Sap34 causes a global reduction in splicing efficiency with
increased intron retention.
supporting_text: deletion of sap34 leads to a global reduction in splicing
efficiency, predominantly associated with increased intron retention
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Direct ortholog functional characterization. Strongly supports
the pre-mRNA splicing core function. Abstract-only in the cache; full text
not yet available.
- id: file:human/GPATCH11/GPATCH11-deep-research-falcon.md
title: Falcon deep research report for GPATCH11
findings:
- statement: GPATCH11 is a non-catalytic regulator of RNA metabolism predicted to
act as a G-patch cofactor that binds and stimulates DEAH/RHA-box RNA helicases.
supporting_text: GPATCH11 functions primarily as a regulator of RNA metabolism
rather than as an enzyme with catalytic activity
- statement: Mouse retina transcriptomics show GPATCH11 loss alters hundreds of
splicing events, supporting a pre-mRNA splicing role.
supporting_text: Transcriptomic analysis of retinas from Gpatch11-mutant mice
revealed 299 altered splicing events affecting 178 genes
- statement: GPATCH11 localizes to centrosomes during mitosis with no kinetochore/
centromere signal, indicating the CENP-Y alias is a misnomer.
supporting_text: GPATCH11 localizes exclusively to centrosomes with no detectable
localization at kinetochores or centromeres
reference_review:
relevance: HIGH
correctness: UNVERIFIED
review_notes: LLM-synthesized deep-research report (Edison/Falcon). It is almost
entirely a synthesis of the primary Zanetti/Perrault 2024 study (PMID:39572588)
plus G-patch family reviews (Bohnsack 2021, Karika 2026), and is consistent
with the independently reviewed primary literature already cited here. The
individual constituent PMIDs were not all independently re-verified against
PubMed for this synthesis, so correctness is left UNVERIFIED; quoted
supporting_text below is verbatim from this report. No claims unique to the
report (i.e. not traceable to PMID:39572588 / PMID:42260140) were used to
change any annotation action.