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

Hypogonadotropic hypogonadism (HH) with severe ataxia, impotence, and dementia has been reported in a handful of patients carrying RNF216 gene variants. However, the underlying molecular mechanism explaining this complex phenotype remains unclear to date. RNF216 encodes a "RING-between-RING"(RBR)-class E3 ubiquitin ligase. Among the targets of RNF216 is Beclin-1, a pivotal regulator of autophagy, particularly within the central nervous system.

(i) To assess the prevalence of RN216 mutations in a large cohort of patients with HH. (ii) To examine the impact on autophagy of identified RNF216 pathogenic variants.

Exome analysis in a monocentric cohort of patients with HH. In vitro functional analysis of RNF216 variants in the regulation of autophagy and cell viability.

Among 1476 patients, we identified a unique NM_207111.4:c.2056C>T:p.(Arg686*) RNF216 variant in the homozygous state in one family with 2 affected patients presenting with HH associated with late-onset ataxia and dementia. We observed that in cells expressing this RNF216 variant, the regulation of autophagy was disrupted, indicating a loss-of-function effect. We demonstrated that inhibiting RNF216 expression decreased cell viability. Z-VAD, a pan-caspase inhibitor, did not protect cells from death, whereas 3-MA, an autophagy inhibitor, prevented cell death. Interestingly, we found that other RNF216 variants reported to be associated with this form of HH had a similar functional impact on autophagy.

Our results suggest that alteration of RNF216 function leads to cell death through an autophagy-mediated mechanism which contributes to combined HH and ataxia and dementia in affected patients.