Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

Laura C. Bott, Mitra Forouhan, Maria Lieto, Ambre J. Sala, Ruth Ellerington, Janel O. Johnson, Alfina A. Speciale, Chiara Criscuolo, Alessandro Filla, David Chitayat, Ebba Alkhunaizi, Patrick Shannon, Andrea H. Nemeth, Francesco Angelucci, Wooi Fang Lim, Pasquale Striano, Federico Zara, Ingo Helbig, Mikko Muona, Carolina CourageAnna Elina Lehesjoki, Samuel F. Berkovic, Kenneth H. Fischbeck, Francesco Brancati, Richard I. Morimoto, Matthew J.A. Wood, Carlo Rinaldi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


The vacuolar H -ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.

Original languageEnglish (US)
Article number245
JournalBrain Communications
Issue number4
StatePublished - 2021


  • Caenorhabditis elegans disease modelling
  • V-ATPase
  • epileptic encephalopathy
  • lysosomal disease
  • organelle acidification

ASJC Scopus subject areas

  • Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience


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