RNF216 Variants Found in Patients With Dementia, Hypogonadotropic Hypogonadism, and Severe Ataxia Deregulate Autophagy

RNF216 (pathogenic variants — RBR-class E3 ubiquitin ligase)

Autophagy dysregulation via direct target Beclin-1 — in vitro functional analysis + screening in a cohort of 1,476 HH patients

RNF216 encodes an RBR-class E3 ubiquitin ligase involved in Gordon-Holmes syndrome (HH, severe ataxia, dementia). The molecular mechanism linking pathogenic variants to the complex phenotype was previously unknown. The authors show that RNF216 directly targets Beclin-1, a pivotal regulator of autophagy in the CNS. In vitro functional analysis demonstrates autophagy dysregulation and impaired cell viability in the presence of pathogenic variants, in the context of screening 1,476 HH patients.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Mechanistically important finding for Gordon-Holmes syndrome: autophagy dysregulation via Beclin-1 explains the progressive neurological involvement. This opens potential therapeutic avenues via autophagy modulation. In diagnostic practice, consider RNF216 in any presentation of HH + ataxia + cognitive decline.

known gene +0; biallelic AR +1; functional autophagy (Beclin-1) +2; 1476-patient cohort +2; mechanism impact +1; J Clin Endocrinol Metab +1