Loss of RUBCN causes autophagy overdrive in a neurodevelopmental disorder with age-dependent neurodegeneration
- 1Department of Neuromuscular disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
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.
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BibTeX
@misc{efthymiou2026loss,
title = {{Loss of RUBCN causes autophagy overdrive in a neurodevelopmental disorder with age-dependent neurodegeneration}},
author = {S. Efthymiou and K. Tabata and H. S. Dafsari and E. Schober and C. Latza and M. Isaoglu and A. Abuelrub and A. Rad and Z. Firoozfar and V. Turchetti and R. Q. Lin and R. Maroofian and S. Wiethoff and E. Afzal and F. Zafar and N. Rana and A. M. McRae and R. Kaiyrzhanov and U. Guliyeva and S. Gulieva and G. Melikishvili and J. Lespinasse and A. Vitobello and A.-S. Denomme-Pichon and I. M. Wentzensen and H. C. Mefford and L. C. Briere and M. A Walker and F. A High and D. A. Sweetser and M. Kendall and M. Franchi and M. Brown and D. Latner and P. Joset and I. Ivanovski and M. Alfadhel and I. Alluhaydan and A. S. Frederiksen and V. Arriens and B. Hanker and K. Mankad and J Guerin},
howpublished = {medRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.26360298},
url = {https://www.medrxiv.org/content/10.64898/2026.08.27.26360298v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Loss of RUBCN causes autophagy overdrive in a neurodevelopmental disorder with age-dependent neurodegeneration
AU - S. Efthymiou
AU - K. Tabata
AU - H. S. Dafsari
AU - E. Schober
AU - C. Latza
AU - M. Isaoglu
AU - A. Abuelrub
AU - A. Rad
AU - Z. Firoozfar
AU - V. Turchetti
AU - R. Q. Lin
AU - R. Maroofian
AU - S. Wiethoff
AU - E. Afzal
AU - F. Zafar
AU - N. Rana
AU - A. M. McRae
AU - R. Kaiyrzhanov
AU - U. Guliyeva
AU - S. Gulieva
AU - G. Melikishvili
AU - J. Lespinasse
AU - A. Vitobello
AU - A.-S. Denomme-Pichon
AU - I. M. Wentzensen
AU - H. C. Mefford
AU - L. C. Briere
AU - M. A Walker
AU - F. A High
AU - D. A. Sweetser
AU - M. Kendall
AU - M. Franchi
AU - M. Brown
AU - D. Latner
AU - P. Joset
AU - I. Ivanovski
AU - M. Alfadhel
AU - I. Alluhaydan
AU - A. S. Frederiksen
AU - V. Arriens
AU - B. Hanker
AU - K. Mankad
AU - J Guerin
PY - 2026
DA - 2026/08/27
PB - medRxiv
DO - 10.64898/2026.08.27.26360298
UR - https://www.medrxiv.org/content/10.64898/2026.08.27.26360298v1
AB - 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.
ER -