Pinard, Amélie;
Ye, Wenlei;
Fraser, Stuart M;
Rosenfeld, Jill A;
Pichurin, Pavel;
Hickey, Scott E;
Guo, Dongchuan;
... Milewicz, Dianna M; + view all
(2023)
Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease.
Brain
, 146
(9)
pp. 3616-3623.
10.1093/brain/awad172.
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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 etiology 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 analyzed 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 harboring these gain-of-function ANO1 variants had classic features of MMD, 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.
| Type: | Article |
|---|---|
| Title: | Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awad172 |
| Publisher version: | https://doi.org/10.1093/brain/awad172 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Genetic heterogeneity, genotype-phenotype, pathogenesis, smooth muscle cells, stroke genetics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10171179 |
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