TY - JOUR
T1 - Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease
AU - University of Washington Center for Mendelian Genomics
AU - Pinard, Amlie
AU - Ye, Wenlei
AU - Fraser, Stuart M.
AU - Rosenfeld, Jill A.
AU - Pichurin, Pavel
AU - Hickey, Scott E.
AU - Guo, Dongchuan
AU - Cecchi, Alana C.
AU - Boerio, Maura L.
AU - Guey, Stphanie
AU - Aloui, Chaker
AU - Lee, Kwanghyuk
AU - Kraemer, Markus
AU - Alyemni, Saleh Omar
AU - Bamshad, Michael J.
AU - Nickerson, Deborah A.
AU - Tournier-Lasserve, Elisabeth
AU - Haider, Shozeb
AU - Jin, Sheng Chih
AU - Smith, Edward R.
AU - Kahle, Kristopher T.
AU - Jan, Lily Yeh
AU - He, Mu
AU - Milewicz, Dianna M.
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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.
AB - 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.
KW - genetic heterogeneity
KW - genotype-phenotype
KW - pathogenesis
KW - smooth muscle cells
KW - stroke genetics
UR - http://www.scopus.com/inward/record.url?scp=85164345512&partnerID=8YFLogxK
U2 - 10.1093/brain/awad172
DO - 10.1093/brain/awad172
M3 - Article
C2 - 37253099
AN - SCOPUS:85164345512
SN - 0006-8950
VL - 146
SP - 3616
EP - 3623
JO - Brain
JF - Brain
IS - 9
ER -