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Article: Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease

TitleRare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease
Authors
Keywordsgenetic heterogeneity
genotype-phenotype
pathogenesis
smooth muscle cells
stroke genetics
Issue Date1-Sep-2023
PublisherOxford University Press
Citation
Brain, 2023, v. 146, n. 9, p. 3616-3623 How to Cite?
Abstract

Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.


Persistent Identifierhttp://hdl.handle.net/10722/338840
ISSN
2023 Impact Factor: 10.6
2023 SCImago Journal Rankings: 4.689
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorPinard, A-
dc.contributor.authorYe, W-
dc.contributor.authorFraser, SM-
dc.contributor.authorRosenfeld, JA-
dc.contributor.authorPichurin, P-
dc.contributor.authorHickey, SE-
dc.contributor.authorGuo, D-
dc.contributor.authorCecchi, AC-
dc.contributor.authorBoerio, ML-
dc.contributor.authorGuey, S-
dc.contributor.authorAloui, C-
dc.contributor.authorLee, K-
dc.contributor.authorKraemer, M-
dc.contributor.authorAlyemni, SO-
dc.contributor.authorBamshad, MJ-
dc.contributor.authorNickerson, DA-
dc.contributor.authorTournier-Lasserve, E-
dc.contributor.authorHaider, S-
dc.contributor.authorJin, SC-
dc.contributor.authorSmith, ER-
dc.contributor.authorKahle, KT-
dc.contributor.authorJan, LY-
dc.contributor.authorHe, M-
dc.contributor.authorMilewicz, DM-
dc.date.accessioned2024-03-11T10:31:56Z-
dc.date.available2024-03-11T10:31:56Z-
dc.date.issued2023-09-01-
dc.identifier.citationBrain, 2023, v. 146, n. 9, p. 3616-3623-
dc.identifier.issn0006-8950-
dc.identifier.urihttp://hdl.handle.net/10722/338840-
dc.description.abstract<p>Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.</p>-
dc.languageeng-
dc.publisherOxford University Press-
dc.relation.ispartofBrain-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectgenetic heterogeneity-
dc.subjectgenotype-phenotype-
dc.subjectpathogenesis-
dc.subjectsmooth muscle cells-
dc.subjectstroke genetics-
dc.titleRare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease-
dc.typeArticle-
dc.identifier.doi10.1093/brain/awad172-
dc.identifier.scopuseid_2-s2.0-85164345512-
dc.identifier.volume146-
dc.identifier.issue9-
dc.identifier.spage3616-
dc.identifier.epage3623-
dc.identifier.eissn1460-2156-
dc.identifier.isiWOS:001033223200001-
dc.identifier.issnl0006-8950-

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