Аңдатпа
Abstract Pathogenic variants in RUBCN , encoding the Run domain Beclin-1 interacting and cysteine-rich domain-containing protein (Rubicon) have been implicated in autosomal recessive spinocerebellar ataxia 15 (SCAR15). However, the molecular mechanisms underlying disease pathogenesis remain poorly understood. Here, we report 18 individuals from 15 unrelated families harbouring biallelic RUBCN variants, who present with an aggressive neurodevelopmental disorder variably characterized by seizures, developmental delay, intellectual disability and movement abnormalities that cause regression, progressive brain atrophy and neurodegenerative features. Through functional characterization, we demonstrate that a subset of disease-associated putative truncating variants disrupt autophagy regulation. In Caenorhabditis elegans models, loss-of-function RUBCN variants result in an increased autophagic flux and impaired neuronal function, recapitulating key features in humans. Correspondingly, cellular assays reveal that nonsense and frameshift RUBCN variants lead to defective autophagy inhibition, underscoring a crucial role for RUBCN as a key negative autophagy regulator. Molecular dynamics simulations rank the eleven missense variants by structural effect, with p.Arg813Trp alone altering the target protein at both the local and the regional level and lying within the RAB7A-binding module that the truncating alleles remove altogether. Our findings establish and expand the RUBCN -related disorders as a clinically and molecularly distinct subset of autophagy-related diseases. By delineating both the genetic landscape and cellular consequences of Rubicon dysfunction, this study enhances our understanding of autophagy-related neurodevelopmental disorders and provides a foundation for future therapeutic investigations.