The ARHGAP33 gene encodes a protein belonging to the sorting nexin family. Similar to other members of this family, the protein contains a phosphoinositide binding phox (PX) domain at its N terminal. The protein also contains SRC homology-3 (SH3) domain, a RHO GTPase-activating protein (GAP) domain, and 22 PxxP motifs in its proline- and serine-rich C-terminal domain. ARHGAP33 is speculated to have GTPase activator activity and is involved in small GTPase mediated signal transduction as well as protein transport. It is believed to play an important role in the regulation of insulin-stimulated glucose transport by acting as a downstream effector of RHOQ/TC10.
The ARHGAP33 gene is located on the long arm of chromosome 19. It spans a length of 14.2 kb of DNA and its coding sequence is spread across 22 exons. The protein product encoded by the gene has a molecular mass of 137 kDa and consists of 1287 amino acids. Several different isoforms of the ARHGAP33 protein exist due to alternative splicing. The gene is found to be overexpressed in the fetal brain and heart.
Anazi et al. (2016) carried out a study to determine the efficiency of genomic tools as a diagnostic test by analyzing 337 patients with Intellectual Disability (ID). The genomic approach was found to have a higher diagnostic yield than standard clinical evaluations (58% vs 16%). Exome sequencing uncovered a homozygous c.1495G>A (p.Val499Met) mutation in the ARHGAP33 gene of a 5-year old boy and his 7-month old sister. The patients belonged to a consanguineous family and both suffered from global developmental delays, seizures, and dysmorphic features. It was noted that ARHGAP33 deficient mice have autism-associated social behavior and abnormal synapse development. Furthermore, the identified amino acid change occurred in the Rho-GAP domain and was predicted to result in the destabilization and deformation of the GTPase binding site.
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