RAB3GAP1 and RAB3GAP2 and the Warburg Micro and Martsolf Syndromes

Abstract

Abstract Warburg Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270) are autosomal recessive neurodevelopmental disorders that may result from the dysregulation of the Rab3 pathway. Inactivating germline mutations in RAB3GAP1, which encodes the catalytic subunit of the heterodimeric Rab3 GTPase-activating pro- tein (Rab3GAP), cause Micro syndrome in approximately 60–70% of cases. Mutations in the noncatalytic subunit, RAB3GAP2, have been associated with Martsolf syndrome. Micro syndrome is a severe disorder characterized by ocular (microphthalmos, microcornea, congenital cataracts, optic atrophy); neurodevelopmental (microcephaly, cortical gyral abnormalities—polymicrogyria, hypoplasia of the cor- pus callosum, severe learning disability, spastic cerebral palsy) and endocrine abnormalities. Martsolf syndrome has an overlapping but less severe phenotype. In both disorders, there is also evidence for locus heterogeneity.