Bohnen, M.S., Ma, L., Zhu, N. et al. (47 more authors) (2018) Loss-of-function ABCC8 mutations in pulmonary arterial hypertension. Circulation: Genomic and Precision Medicine, 11 (10). e002087. ISSN 2574-8300
Abstract
Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target.
Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.
Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.
Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 American Heart Association, Inc. This is an author produced version of a paper subsequently published in Circulation: Genomic and Precision Medicine. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | electrophysiology; genetics; humans; hypertension, pulmonary; ion channels |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number BRITISH HEART FOUNDATION FS/13/48/30453 MEDICAL RESEARCH COUNCIL MR/K020919/1 BRITISH HEART FOUNDATION NONE BRITISH HEART FOUNDATION PG/11/116/29288 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 29 Nov 2018 10:51 |
Last Modified: | 12 Apr 2019 00:42 |
Published Version: | https://doi.org/10.1161/CIRCGEN.118.002087 |
Status: | Published |
Publisher: | American Heart Association |
Refereed: | Yes |
Identification Number: | 10.1161/CIRCGEN.118.002087 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:139316 |