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

Show full item record



Italian Undiagnosed Dis Network , V-ATPase Consortium , Bott , L C , Forouhan , M , Lieto , M , Muona , M , Courage , C , Lehesjoki , A-E & Rinaldi , C 2021 , ' Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy ' , Brain communications , vol. 3 , no. 4 , 245 .

Title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy
Author: Italian Undiagnosed Dis Network; V-ATPase Consortium; Bott, Laura C.; Forouhan, Mitra; Lieto, Maria; Muona, Mikko; Courage, Carolina; Lehesjoki, Anna-Elina; Rinaldi, Carlo
Contributor organization: Research Programs Unit
University of Helsinki
Department of Medical and Clinical Genetics
Date: 2021-10-01
Language: eng
Number of pages: 14
Belongs to series: Brain communications
ISSN: 2632-1297
Abstract: Bott et al. here reports that de novo and biallelic variants in ATP6V0A1 gene affect the ability of the V-ATPase complex to translocate protons and acidify the endolysosomal compartment in neurons, causing a severe neurological phenotype ranging from developmental and epileptic encephalopathy to progressive myoclonus epilepsy. 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.
Subject: V-ATPase
epileptic encephalopathy
Caenorhabditis elegans disease modelling
organelle acidification
lysosomal disease
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

Files in this item

Total number of downloads: Loading...

Files Size Format View
fcab245.pdf 1.311Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record