The RAB3GAP1 gene encodes a protein, which has a specificity for the members of the RAB3 protein family, and catalyzes the conversion of the active RAB3-GTP protein to its inactive RAB3-GDP form. The RAB proteins are prime regulators of membrane transport in both the exocytic and endocytic pathways, and are believed to participate in neurodevelopmental processes such as proliferation, migration and differentiation before synapse formation, and nonsynaptic vesicular release of neurotransmitters. The main function of the RAB3GAP1 protein, therefore, is in the regulated exocytosis of neurotransmitters and hormones. The gene plays a very important role in normal eye and brain development.
Mutations in the RAB3GAP1 gene have been implicated in Warburg micro syndrome, characterized by neurodevelopmental and ocular defects. It is postulated that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors, due to the loss of function of the RAB3GAP1 gene.
The RAB3GAP1 gene has been mapped to gene locus 2q21.3, and has been found to contain 24 exons. The catalytic subunit encoded by this gene forms a complex with the non-catalytic RAB3GAP150 (150 KDa) subunit, coded for by a different gene on chromosome 1. The catalytic activity of the RAB3GAP1 protein is localized in the C-Terminal region, and therefore, almost all mutations in the gene affect the catalytic activity.
A Lebanese kindred, affected with Warburg micro syndrome was studied for mutations in the RAB3GAP1 gene by Aligianis et al. (2005). All affected members were found to carry a mutation (2011C-T) at exon 18 resulting in an arg671-to-ter (R671X) substitution.
Aligianis et al. (2005) mapped the gene for Warburg micro syndrome to 2q21.3 in five kindreds affected by the disease, including one kindred from Morocco. Sequencing of the exons and the flanking sequences revealed no mutations in MGAT5, ACMSD, CCNT2 and other genes. However, the exons of the RAB3GAP1 gene showed mutations in all the kindreds. The Moroccan kindred was shown to have a four bp (ACTG) deletion at position 475-478 at exon 6.