Disease relevance of RAB3GAP1

• We identified a homozygous missense mutation in the noncatalytic subunit (RAB3GAP2) of RAB3GAP that results in abnormal splicing in a family with congenital cataracts, hypogonadism, and mild mental retardation (Martsolf syndrome) [1].

High impact information on RAB3GAP1

• Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome [2].
• Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia [2].
• We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome [2].
• We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130(Cas)) [3].
• We performed messenger RNA-expression studies of RAB3GAP1 and RAB3GAP2 orthologues in Danio rerio embryos and demonstrated that, whereas developmental expression of rab3gap1 was generalized (similar to that reported elsewhere in mice), rab3gap2 expression was restricted to the central nervous system [1].

Biological context of RAB3GAP1

• RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively [1].
• These findings suggest that RAB3GAP dysregulation may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome [1].
• Recently, mutations in the catalytic subunit of RAB3GAP (RAB3GAP1), a key regulator of calcium-mediated hormone and neurotransmitter exocytosis, were reported in Warburg micro syndrome, a severe neurodevelopmental condition with overlapping clinical features [1].
• P62, P68, and P130, which exhibited increased tyrosine phosphorylation upon stimulation with YFLLRNP, were found in the cytoskeleton [4].

Associations of RAB3GAP1 with chemical compounds

• We propose that Rab3-GAP, like Ras- and Rho-GAPs, stabilizes the transition state of Rab3 and provides a critical arginine residue to accelerate the GTPase reaction [5].

Physical interactions of RAB3GAP1

• Therefore, the Rab3-GAP-binding site involves the switch I region of Rab3 and overlaps with the Rabphilin-binding domain [5].

Other interactions of RAB3GAP1

• Rab3 GEP stimulates the conversion of the GDP-bound inactive form to the GTP-bound active form, whereas Rab3 GAP stimulates the reverse reaction [6].
• Furthermore, Rabphilin, a putative target of Rab3, inhibited the activity of Rab3-GAP on Rab3 [5].
• CONCLUSION: These results indicate that rabconnectin-3 consists of the alpha and beta subunits and binds directly Rab3 GEP through the beta subunit and indirectly Rab3 GAP through an unidentified molecule(s) [7].

Analytical, diagnostic and therapeutic context of RAB3GAP1

• By Western blot analysis with anti-MAP kinase antibodies, we demonstrate that p42 is one member of the mitogen-activating protein kinase, namely the p42MAPK [8].

References