TY - JOUR
T1 - Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy
AU - Bott, Laura C.
AU - Forouhan, Mitra
AU - Lieto, Maria
AU - Sala, Ambre J.
AU - Ellerington, Ruth
AU - Johnson, Janel O.
AU - Speciale, Alfina A.
AU - Criscuolo, Chiara
AU - Filla, Alessandro
AU - Chitayat, David
AU - Alkhunaizi, Ebba
AU - Shannon, Patrick
AU - Nemeth, Andrea H.
AU - Angelucci, Francesco
AU - Lim, Wooi Fang
AU - Striano, Pasquale
AU - Zara, Federico
AU - Helbig, Ingo
AU - Muona, Mikko
AU - Courage, Carolina
AU - Lehesjoki, Anna Elina
AU - Berkovic, Samuel F.
AU - Fischbeck, Kenneth H.
AU - Brancati, Francesco
AU - Morimoto, Richard I.
AU - Wood, Matthew J.A.
AU - Rinaldi, Carlo
N1 - Publisher Copyright:
© The Author(s) (2021).
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Caenorhabditis elegans disease modelling
KW - V-ATPase
KW - epileptic encephalopathy
KW - lysosomal disease
KW - organelle acidification
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U2 - 10.1093/braincomms/fcab245
DO - 10.1093/braincomms/fcab245
M3 - Article
C2 - 34909687
AN - SCOPUS:85127370437
SN - 2632-1297
VL - 3
JO - Brain Communications
JF - Brain Communications
IS - 4
M1 - 245
ER -