Affinage

RAB3GAP2

Rab3 GTPase-activating protein non-catalytic subunit · UniProt Q9H2M9

Length
1393 aa
Mass
156.0 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB3GAP2 is a regulatory component of the RAB3GAP complex that links RAB GTPase regulation to autophagy, secretion, and vascular and lens cell homeostasis (PMID:25495476, PMID:41678332). Together with RAB3GAP1, it modulates autophagosomal biogenesis under basal and rapamycin-induced conditions in a manner that depends on the GTPase-activating activity of RAB3GAP1 but is independent of RAB3, with the complex colocalizing with Atg8-family members at lipid droplets (PMID:25495476). Its expression is positively controlled by the transcription factor FOXC1, coupling it to Myocilin secretion and ocular exocytic/endocytic pathways relevant to glaucoma (PMID:28575017). In skeletal muscle microvascular endothelium, RAB3GAP2 acts as a negative regulator of endothelial proliferation and angiogenesis, restraining tube formation and the secretion of angiogenic factors including CD70 and TNC, possibly through RAB18 (PMID:41678332). In lens epithelial cells it suppresses oxidative stress and apoptosis by restraining JNK/STAT3 signaling that drives Mfn2 transcription and Mfn2-mediated mitochondrial autophagy (PMID:41271057). Loss-of-function mutations in RAB3GAP2 cause Warburg Micro syndrome, whereas milder hypomorphic mutations cause Martsolf syndrome, defining a severity continuum set by residual protein function (PMID:23420520, PMID:20967465).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 Low

    Establishing that a severe RAB3GAP2 lesion can produce disease addressed whether RAB3GAP2 mutation alone causes the full Micro syndrome phenotype.

    Evidence Sanger sequencing of an in-frame deletion in a consanguineous family with clinical phenotyping

    PMID:20967465

    Open questions at the time
    • Single family; no biochemical assay of the mutant protein's activity
    • Does not define the molecular function disrupted by the deletion
  2. 2013 Medium

    Genotype-phenotype correlation across many families resolved how mutation severity maps onto clinical outcome, establishing the Micro/Martsolf continuum.

    Evidence Mutational analysis of 144 Micro and 9 Martsolf families with variant database curation

    PMID:23420520

    Open questions at the time
    • No direct biochemical assay of RAB3GAP2 activity
    • Mechanism connecting residual function to phenotype severity not defined
  3. 2014 Medium

    Demonstrating that the RAB3GAP complex modulates autophagosome biogenesis revealed a cellular function beyond RAB3 regulation, dependent on RAB3GAP1 catalytic activity but independent of RAB3.

    Evidence C. elegans genetics, human fibroblast knockdown, autophagy marker puncta analysis, and lipid droplet colocalization

    PMID:25495476

    Open questions at the time
    • The relevant RAB substrate for autophagy is unidentified
    • Specific contribution of RAB3GAP2 versus RAB3GAP1 to the autophagy phenotype not separated
  4. 2017 Medium

    Identifying FOXC1 as a positive regulator of RAB3GAP2 expression connected the gene to transcriptional control of ocular secretion and glaucoma-relevant Myocilin handling.

    Evidence FOXC1 level manipulation and Myocilin secretion assays in ocular cell lines

    PMID:28575017

    Open questions at the time
    • No reconstitution of RAB3GAP2 enzymatic role in secretion
    • Direct versus indirect transcriptional control not distinguished
  5. 2025 Medium

    Lens cell models defined a signaling axis by which RAB3GAP2 restrains JNK/STAT3-driven Mfn2-mediated mitophagy, explaining its protective role against oxidative stress and apoptosis.

    Evidence siRNA silencing in NaIO3-induced cataract cell and mouse models with JNK inhibitor and Mfn2 rescue, ROS and mitochondrial membrane potential assays

    PMID:41271057

    Open questions at the time
    • Molecular step linking RAB3GAP2 to JNK activation not defined
    • Whether the effect requires GAP activity is untested
  6. 2026 Medium

    Endothelial studies established RAB3GAP2 as a negative regulator of proliferation and angiogenesis, expanding its role to vascular biology and secreted angiogenic factor control.

    Evidence siRNA knockdown in human endothelial cells, in vitro proliferation/tube formation, in vivo mouse endothelial density, secretome proteomics and eQTL analysis

    PMID:41678332

    Open questions at the time
    • RAB18 involvement is only suggested, not demonstrated mechanistically
    • Direct link between GAP activity and angiogenic factor secretion unestablished
  7. 2026 Medium

    A splice-site variant causing exon 3 skipping demonstrated a concrete loss-of-function mechanism for pathogenic RAB3GAP2 alleles.

    Evidence Patient leukocyte RT-PCR and minigene splicing assay in HEK293T and HeLa cells

    PMID:42106822

    Open questions at the time
    • Truncated protein product not directly detected or functionally assayed
    • Tissue-specific consequences not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RAB3GAP2's non-catalytic role within the complex mechanistically couples its established cellular functions (autophagy, angiogenesis, mitophagy) to specific RAB substrates.
  • No structural model of the RAB3GAP2/RAB3GAP1 complex in the corpus
  • RAB substrate specificity underlying the autophagy and endothelial phenotypes not defined
  • Direct biochemical assay of RAB3GAP2 contribution to GAP activity absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005811 lipid droplet 1
Pathway
R-HSA-9612973 Autophagy 1
Partners
RAB18RAB3GAP1
Complex memberships
RAB3GAP complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 RAB3GAP1 and RAB3GAP2 form a complex (RAB3GAP complex) that modulates autophagosomal biogenesis at basal and rapamycin-induced conditions; their autophagy modulatory activity depends on the GTPase-activating activity of RAB3GAP1 but is independent of the RAB GTPase RAB3. Significant levels of RAB3GAP1/2 colocalize with Atg8 family members at lipid droplets. C. elegans genetics and human primary fibroblasts; correlation with ATG3, ATG16L1, ATG5 puncta analysis; colocalization imaging; epistasis with FEZ1/FEZ2 Autophagy Medium 25495476
2017 FOXC1 positively regulates RAB3GAP2 (and RAB3GAP1) expression, and this regulation affects secretion of Myocilin (MYOC); modulation of RAB3GAP2 expression by FOXC1 links it to exocytosis/endocytosis pathways relevant to glaucoma. Biochemical and molecular techniques including gene expression manipulation (FOXC1 level alteration) and MYOC secretion assays in ocular cell lines PloS one Medium 28575017
2026 RAB3GAP2 is expressed predominantly in skeletal muscle microvascular endothelium and acts as a negative regulator of endothelial cell proliferation and angiogenesis; experimental knockdown of RAB3GAP2 in human endothelial cells increased proliferation, tube formation in vitro, and in vivo endothelial cell density in mice, and regulated secreted angiogenic factors (CD70, TNC), possibly mediated through RAB18. siRNA knockdown in human endothelial cells; in vitro proliferation and tube formation assays; in vivo mouse endothelial density measurement; secretome/proteomics of conditioned medium; eQTL analysis; immunofluorescence localization Cell reports Medium 41678332
2025 RAB3GAP2 silencing in lens epithelial cell cataract models activates the JNK/STAT3 signaling pathway, increasing Mfn2 transcription and promoting Mfn2-mediated mitochondrial autophagy, thereby reducing oxidative stress and apoptosis; inhibition of JNK (SP600125) or Mfn2 silencing abrogated these effects both in vitro and in a mouse cataract model. siRNA silencing in NaIO3-induced cataract cell models and mouse cataract model; RNA sequencing; JNK inhibitor (SP600125); Mfn2 siRNA; ROS and mitochondrial membrane potential assays; STAT3 nuclear translocation; in vivo mouse experiments International journal of biological macromolecules Medium 41271057
2026 A RAB3GAP2 splice site variant (c.304+5G>T) causes aberrant splicing with exon 3 skipping, demonstrated by RT-PCR in patient leukocytes and a minigene assay in HEK293T and HeLa cells, predicting a truncated, loss-of-function protein. RT-PCR on patient peripheral blood; minigene splicing assay in HEK293T and HeLa cells; bioinformatics splice prediction tools BMC medical genomics Medium 42106822
2013 Genotype-phenotype analysis of mutations in RAB3GAP1, RAB3GAP2, and RAB18 established that loss-of-function mutations in RAB3GAP2 cause Warburg Micro syndrome, while hypomorphic (milder) RAB3GAP2 mutations cause the less severe Martsolf syndrome, indicating a phenotypic severity continuum determined by the nature of the mutation and residual protein function. Mutational analysis of 144 Micro and 9 Martsolf families; Leiden Open source Variation Database curation; genotype-phenotype correlation Human mutation Medium 23420520
2010 A homozygous in-frame deletion in RAB3GAP2 (p.Phe167_Thr169del) causes Warburg Micro syndrome, demonstrating that functionally severe RAB3GAP2 mutations (not only hypomorphic ones) can produce the full Micro syndrome phenotype, establishing that RAB3GAP2 loss-of-function severity determines clinical outcome. Sanger sequencing of RAB3GAP2 in a consanguineous family; clinical phenotyping Human genetics Low 20967465

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in warburg micro syndrome and Martsolf syndrome. Human mutation 110 23420520
2014 RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy. Autophagy 75 25495476
2010 A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Human genetics 72 20967465
2012 RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes. Biochemical Society transactions 23 23176487
2017 FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25. PloS one 9 28575017
2020 Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome. Cold Spring Harbor molecular case studies 6 32376645
2018 Case report of four siblings in southeast Turkey with a novel RAB3GAP2 splice site mutation: Warburg micro syndrome or Martsolf syndrome? Ophthalmic genetics 6 29419336
2024 Three Iranian patients with rare subtypes of hereditary spastic paraplegia (HSP): SPG76, SPG56, and SPG69. Neurogenetics 2 39607444
2025 RAB3GAP2 dysregulation in adult T-cell leukemia/lymphoma (ATLL) compared to acute lymphoblastic leukemia (ALL): a molecular perspective. BMC research notes 1 39838474
2026 RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio. Cell reports 0 41678332
2026 Functional analysis of a novel splice site variant of RAB3GAP2 in a fetus with congenital cataracts. BMC medical genomics 0 42106822
2025 RAB3GAP2 silencing alleviates oxidative stress in cataracts by enhancing Mfn2-mediated mitochondrial autophagy by activating JNK/STAT3. International journal of biological macromolecules 0 41271057

Missed literature

Know a paper Affinage missed for RAB3GAP2? Flag it for the maintainers and the community.

No submissions yet.