ArticleCirculation. Genomic and precision medicine2018
Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension.
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57 citing papers in PubMed, 78 citations in OpenAlex.
- Trial
- Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD.medRxiv : the preprint server for health sciences · 2026Article
- Expanding the genetic burden of low-evidence genes in pulmonary arterial hypertension.European journal of human genetics : EJHG · 2026Article
- Molecular-Genetic Basis of Pulmonary Arterial Hypertension (PAH).Current issues in molecular biology · 2026Review
- The Role of Genetics in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.Pediatric cardiology · 2026Observational
- The exquisite link between potassium homeostasis regulation and cardiovascular health: exploration and analysis.Frontiers in physiology · 2026Review
- Systemic Sclerosis Associated Pulmonary Arterial Hypertension with Venous Involvement - a Novel ABCC8 Pathogenic Variant.Arquivos brasileiros de cardiologia · 2026Article
- Gene and metabolite changes triggered by downregulation of JUNB and ZNF281 in idiopathic pulmonary arterial hypertension: potential mechanisms revealed by multi-omics study.Translational pediatrics · 2025Article
- Pathogenic variation in insulin resistance genes is common in polycystic ovary syndrome (PCOS): a strategy for causal gene discovery using whole-exome sequencing (WES) in complex traits.medRxiv : the preprint server for health sciences · 2025Article
- Genome-Wide Association Study of Atrial Fibrillation Recurrence After Radiofrequency Catheter Ablation in a Japanese Population.Journal of cardiovascular electrophysiology · 2025Article
- Bayliss-Starling Prize Lecture: KThe Journal of physiology · 2025Article
- Review
- Mechanisms and treatment of pulmonary arterial hypertension.Nature reviews. Cardiology · 2025Review
- Uncovering Candidate Genes Associated with Cardiovascular Disease in Patients with Arteriovenous Fistula and End-Stage Renal Disease.Cardiorenal medicine · 2025Article
- Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series).Pulmonary circulation · 2025Article
- Whole-exome sequencing reveals the genetic causes and modifiers of moyamoya syndrome.Scientific reports · 2024Article
- Seeing pulmonary hypertension through a paediatric lens: a viewpoint.The European respiratory journal · 2024Article
- Endothelial Function in Pulmonary Arterial Hypertension: From Bench to Bedside.Journal of clinical medicine · 2024Review
- Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.International journal of molecular sciences · 2024Article
- Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia.BMC endocrine disorders · 2024Article
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Authors and funding
50 authors at 1 institution in 1 country.
Michael S BohnenDepartment of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY.
Lijiang MaDepartment of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.
Na ZhuDepartment of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.
Hongjian QiDepartment of Applied Physics and Applied Mathematics (H.Q., Y.S.), Columbia University, New York, NY.
Conor McClenaghanDepartment of Cell Biology and Physiology (C.M., C.G.N.) and Center for the Investigation of Membrane Excitability Diseases (C.M., C.G.N.), Washington University School of Medicine, Washington University in St. Louis, MO.
Claudia Gonzaga-JaureguiRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
Frederick E DeweyRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
John D OvertonRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
Jeffrey G ReidRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
Alan R ShuldinerRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
Aris BarasRegeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).
Kevin J SampsonDepartment of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY.
Marta BledaDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Charaka HadinnapolaDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Matthias HaimelDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Harm J BogaardVU University Medical Center, Amsterdam, the Netherlands (H.J.B., A.C.H., A.V.N.).
Colin ChurchGolden Jubilee National Hospital, Glasgow, Scotland (C.C., A.J.P.).
Gerry CoghlanRoyal Free Hospital, London, England (G.C.).
Paul A CorrisNewcastle University (P.A.C.) and Newcastle upon Tyne Hospitals National Health Service Foundation Trust (P.A.C.), United Kingdom.
Mélanie EyriesDépat de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (M.E., F.S.) and UMR_S 1166-ICAN, INSERM (Institut National de la Santé et de la Recherche Médicale) (M.E., F.S.), UPMC (Pierre and Marie Curie University) Sorbonne Universités, France.
J Simon R GibbsNational Heart and Lung Institute, Imperial College London, United Kingdom (J.S.R.G., S.J.W.).
Barbara GirerdAP-HP (Assistance Publique - Hôpitaux de Paris), Centre de référence de l'hypertension pulmonaire sévère, INSERM UMR_S 999, Hôpital Bicêtre, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (B.G., M.H., C.G., D.M.).
Arjan C HouwelingVU University Medical Center, Amsterdam, the Netherlands (H.J.B., A.C.H., A.V.N.).
Marc HumbertAP-HP (Assistance Publique - Hôpitaux de Paris), Centre de référence de l'hypertension pulmonaire sévère, INSERM UMR_S 999, Hôpital Bicêtre, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (B.G., M.H., C.G., D.M.).
Christophe GuignabertAP-HP (Assistance Publique - Hôpitaux de Paris), Centre de référence de l'hypertension pulmonaire sévère, INSERM UMR_S 999, Hôpital Bicêtre, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (B.G., M.H., C.G., D.M.).
David G KielySheffield Clinical Research Facility, Royal Hallamshire, Sheffield, United Kingdom (D.G.K.).
Allan LawrieDepartment of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom (A.L.).
Rob V MacKenzie RossRoyal United Bath Hospitals, Bath, United Kingdom (R.V.M.R., J.S.).
Jennifer M MartinDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
David MontaniAP-HP (Assistance Publique - Hôpitaux de Paris), Centre de référence de l'hypertension pulmonaire sévère, INSERM UMR_S 999, Hôpital Bicêtre, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France (B.G., M.H., C.G., D.M.).
Andrew J PeacockGolden Jubilee National Hospital, Glasgow, Scotland (C.C., A.J.P.).
Joanna Pepke-ZabaPapworth Hospital, Cambridge, United Kingdom (J.P.-Z., M.T.).
Florent SoubrierDépat de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (M.E., F.S.) and UMR_S 1166-ICAN, INSERM (Institut National de la Santé et de la Recherche Médicale) (M.E., F.S.), UPMC (Pierre and Marie Curie University) Sorbonne Universités, France.
Jay SuntharalingamRoyal United Bath Hospitals, Bath, United Kingdom (R.V.M.R., J.S.).
Mark ToshnerDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Carmen M TreacyDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Richard C TrembathDivision of Genetics and Molecular Medicine, King's College London, London, England (R.C.T.).
Anton Vonk NoordegraafVU University Medical Center, Amsterdam, the Netherlands (H.J.B., A.C.H., A.V.N.).
John WhartonDepartment of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom (J.W., M.R.W.).
Martin R WilkinsDepartment of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom (J.W., M.R.W.).
Stephen J WortNational Heart and Lung Institute, Imperial College London, United Kingdom (J.S.R.G., S.J.W.).
Katherine YatesDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Stefan GräfDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Nicholas W MorrellDepartment of Medicine (M.B., C.H., M.H., J.M.M., M.T., C.M.T., K.Y., S.G., N.W.M.), University of Cambridge, United Kingdom.
Usha KrishnanDepartment of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.
Erika B RosenzweigDepartment of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.
Yufeng ShenDepartment of Applied Physics and Applied Mathematics (H.Q., Y.S.), Columbia University, New York, NY.
Colin G NicholsDepartment of Cell Biology and Physiology (C.M., C.G.N.) and Center for the Investigation of Membrane Excitability Diseases (C.M., C.G.N.), Washington University School of Medicine, Washington University in St. Louis, MO.
Robert S KassDepartment of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY.
Wendy K ChungDepartment of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.
University of Cambridge · GB
Funding
RESEARCH TRAININGP30DK026687 · NIDDK · ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS · PI Anthony W Ferrante, DYMPNA GALLAGHER · 1986 to 2026
$33.0MPulmonary Hypertension Breakthrough InitiativeR24HL123767 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI ALDRED, MICHEALA A, ERZURUM, SERPIL C. · 2014 to 2017
$10.1MRole of vascular KATP channels in Alzheimer’s neurodegeneration and dementiaR35HL140024 · NHLBI · WASHINGTON UNIVERSITY · PI NICHOLS, COLIN G · 2018 to 2023
$5.9MATP-SENSITIVE POTASSIUM CHANNELS IN THE HEARTR01HL045742 · NHLBI · WASHINGTON UNIVERSITY · PI NICHOLS, COLIN G · 1991 to 2016
$3.6MGENETIC ASPECTS OF PULMONARY HYPERTENSIONR01HL060056 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MORSE, JANE H · 1999 to 2007
$2.9MIntegrate cancer genomics data in geneticstudies and diagnosis of developmental disordersR01GM120609 · NIGMS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI SHEN, YUFENG · 2017 to 2021
$1.7MTASK-1 Mutation as a Cause of Pulmonary Arterial HypertensionF30HL129656 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BOHNEN, MICHAEL · 2015 to 2017
$130kBritish Heart Foundation FS/13/48/30453British Heart Foundation SP/12/12/29836Department of HealthMedical Research Council MR/K020919/1NHLBI NIH HHS F30 HL129656NHLBI NIH HHS R01 HL045742NHLBI NIH HHS R01 HL060056NHLBI NIH HHS R24 HL123767NHLBI NIH HHS R35 HL140024NIDDK NIH HHS P30 DK026687NIGMS NIH HHS R01 GM120609Wellcome Trust
Abstract
backgroundIn 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.
methodsExome 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.
resultsWe 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.
conclusionsNovel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.
Indexed as
ExomeMutation, MissenseAdultAmino Acid SubstitutionChildDNA Mutational AnalysisFamilial Primary Pulmonary HypertensionFemaleHumansMaleSulfonylurea ReceptorsABCC8 protein, humanSulfonylurea Receptorselectrophysiologygeneticshumanshypertension, pulmonaryion channels
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