This report describes Warburg micro syndrome 2 (WARBM2), a subtype of Warburg micro syndrome; WARBM2 exhibits autosomal recessive inheritance. The human gene implicated in this disease is RAB3GAP2, which encodes the regulatory subunit of the RAB3GAP complex; the RAB3GAP complex regulates several classes of Rab GTPases, including RAB18. There is a single orthologous gene in Drosophila, Rab3-GAP,for which a number of genetic reagents have been generated, including RNAi-targeting constructs, alleles caused by insertional mutagenesis, and a targeted CRISPR knockout construct.
The human RAB3GAP2 has not been introduced into flies.
Animals hemizygous for a strong loss-of-function allele of Dmel\Rab3-GAP exhibit a progressive locomotor-defective phenotype. Subcellular localization of Rab3-GAP and impact on autophagic processes have been characterized and compared with similar assays for Dmel\Rab18. These data suggest that the Rab3GAP‐Rab18 module regulates autolysosomal maturation.
[updated Feb. 2021 by FlyBase; FBrf0222196]
Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010; pubmed:20512159). [from MIM:600118; 2021.02.02]
[WARBURG MICRO SYNDROME 2; WARBM2](https://omim.org/entry/614225)
[RAB3 GTPase-ACTIVATING PROTEIN, NONCATALYTIC SUBUNIT; RAB3GAP2](https://omim.org/entry/609275)
Martsolf syndrome (MIM:212720), a clinically overlapping but milder disorder, is also caused by mutation in the RAB3GAP2 gene. [from MIM:614225; 2021.02.02]
Micro syndrome-2 (WARBM2) is caused by homozygous mutation in the RAB3GAP2 gene. [from MIM:614225; 2021.02.02]
RAB3GAP2 encodes a regulatory subunit of a GTPase-activating protein (GAP) complex that has specificity for Rab3 subfamily. [Gene Cards, RAB3GAP2; 2021.02.02]
RAB3GAP1 and RAB3GAP2 form a binary 'RAB3GAP' complex that functions as a guanine-nucleotide exchange factor (GEF) for RAB18. Warburg Micro syndrome can be caused directly by loss of RAB18, or indirectly through loss of RAB18 regulators RAB3GAP1,2 or TBC1D20. (Handley et al., 2015; pubmed:26063829).
The Rab3GAP1,2 complex acts as a bivalent Rab regulator: In addition to its GEF function toward Rab18, it also serves as a GAP for Rab3 (FBrf0247573 and references cited therein).
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human RAB3GAP2 (1 Drosophila to 1 human). Dmel\Rab3-GAP shares 28% identity and 46% similarity with the human gene.
