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

AbstractMoyamoya 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 inANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, andANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additionalANO1 rare variants were identified in moyamoya disease families.TheANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, includingANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-functionANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation.Our studies support thatANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation.

Source: Brain - May 30, 2023 Category: Neurology Source Type: research