Loss of RUBCN causes autophagy overdrive in a neurodevelopmental disorder with age-dependent neurodegeneration.

RUBCN

Biallelic loss-of-function RUBCN variants abolishing autophagy inhibition, with increased autophagic flux

This preprint reports 18 individuals from 15 unrelated families with biallelic RUBCN variants, a gene previously implicated in autosomal recessive spinocerebellar ataxia type 15 (SCAR15). They present with an aggressive neurodevelopmental disorder variably combining seizures, developmental delay, intellectual disability and movement abnormalities, with regression, progressive brain atrophy and neurodegenerative features. In C. elegans, loss-of-function variants increase autophagic flux and impair neuronal function, and cellular assays show that nonsense and frameshift variants fail to inhibit autophagy. Molecular dynamics simulations rank the eleven missense variants by structural effect: only p.Arg813Trp alters the protein at both local and regional levels, within the RAB7A-binding module that truncating alleles remove.

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

A notable phenotypic expansion: a gene known for recessive ataxia turns out to cause an aggressive neurodevelopmental disorder with regression and neurodegeneration, broadening how RUBCN should be read on a paediatric exome or genome. The proposed mechanism is autophagy overdrive through loss of a negative regulator, rather than an autophagy deficit, a therapeutic lead the authors defer to future work. Preprint; how many missense variants are truly pathogenic remains uncertain, as only one stands out in molecular dynamics.

Analysis by Dr Thibaut Benquey