De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

Abstract

By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function.

Paroxysmal Movement Disorders

“…RHOBTB2 (Chr 8:22,987,250-23,020,198, MIM: 607352) Heterozygous missense variants in Rho-related BTB domaincontaining protein 2 (RHOBTB2) were reported in 2018 in 13 individuals with DEEs (102, 103). In the initial reports, 11/13 had a movement disorder (dystonia, dyskinesia, chorea and stereotypies), described as paroxysmal in 4/11 (paroxysmal dyskinesia, dystonic-athetoid attacks) (5,38,103). Subsequently, two case reports focusing on the PxMDs have been published, including a patient with paroxysmal dyskinesia and developmental delay without epilepsy (38,39).…”

Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation

“…Three children with a RHOBTB2 mutation were identified in a cohort of 1,230 children with infantile or early-childhood epilepsy. 2 It has been found that the altered protein RHOBTB2 is relatively resistant to degradation, leading to overexpression of the altered protein. In Drosophila, overexpression of the ortholog RhoBTB is associated with seizure susceptibility and severe locomotor defects.…”

“…It seems that children with a RHOBTB2 mutation do not show stable intellectual impairment, and several show regression-or stagnation-associated with the occurrence of seizures or acute encephalopathy. 1,2,9 When the seizures occur at young age, this regression or stagnation is possibly not recognized.…”

“…Recently, 3 RHOBTB2 patients with acute encephalopathy and febrile epileptic status were described. 2 All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.…”

Translational Genomics in Neurocritical Care: a Review

“…Less common diseases and conditions that one may find in a neurocritical care unit are doubly disadvantaged, as even larger sample sizes are required for sequencing analyses than GWAS, due to the need for many observations to identify rare exonic or intronic variants associated with disease (17,36). As pricing models improve and larger and larger community or hospital-based cohorts receive sequencing through clinical or biobanking efforts, it is hoped that even uncommon conditions such as subarachnoid hemorrhage or status epilepticus will benefit from the insights achievable through sequencing analysis, where case/control and smaller sequencing studies have shown promise (37,38).…”