Molecular characteristics
RHOBTB2 encodes Rho-related BTB (bric-a-brac, tramtrack, broad complex) domain-containing protein 2. RHOBTB2 is an atypical Rho GTPase family member protein, which was identified as a tumor suppressor gene, DBC2 (deleted in breast cancer 2). RHOBTB2 acts as a substrate-recruiting adaptor for the Cullin-3 E3 ubiquitin ligase complex. Indeed, RHOBTB2 itself is the direct substrate for Cullin-3 and is degraded by the ubiquitin-proteasome system, leading to low RHOBTB2 protein levels.
RHOBTB2-related disorders are caused by de novo heterozygous missense mutations in the RHOBTB2 gene. Most mutations are clustered and recurrent. R489 is the most frequent mutational hotspot, as 15 of 31 (48.4%) patients carry mutations affecting the R489 residue (based on NM_015178.3 reference sequence).
Suspected pathophysiologic mechanism
Previous studies have shown that CUL3 complex-dependent proteasomal degradation of mutant RHOBTB2 proteins is impaired, while binding to CUL3 was unaffected, resulting in higher protein levels. In addition, overexpression of RhoBTB, a Drosophila ortholog of RHOBTB2, leads to seizure susceptibility and marked locomotor impairment. These findings suggest that the increased RHOBTB2 levels caused by mutations may be related to neurological abnormalities.
Diagnostic testing
Most patients are diagnosed though next-generation sequencing methods such as whole-exome sequencing.