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

2021

Bott, Laura C

Forouhan, Mitra

Lieto, Maria

Sala, Ambre J

Ellerington, Ruth

Johnson, Janel O

Speciale, Alfina A

Criscuolo, Chiara

Filla, Alessandro

Chitayat, David

Alkhunaizi, Ebba

Shannon, Patrick

Nemeth, Andrea H

Angelucci, Francesco

Lim, Wooi Fang

Striano, Pasquale

Zara, Federico

Helbig, Ingo

Muona, Mikko

Courage, Carolina

Lehesjoki, Anna-Elina

Berkovic, Samuel F

Fischbeck, Kenneth H

Brancati, Francesco

Morimoto, Richard I

Wood, Matthew J A

Rinaldi, Carlo

Caenorhabditis elegans disease modelling

V-ATPase

epileptic encephalopathy

lysosomal disease

organelle acidification

Journal Article

https://orcid.org/0000-0003-4014-3113

https://orcid.org/0000-0003-4580-841X

https://orcid.org/0000-0002-6065-1476

10.1093/braincomms/fcab245

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.

link

Brain Communications 2021; 3(4): fcab245

Brain Communications