Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d685932e710">Background:</h5> <p id="P1">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, due to mutations in <i>KCNK3</i>, was identified as a genetic cause and pharmacological target. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d685932e718">Methods:</h5> <p id="P2">Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult onset group I pulmonary arterial hypertension 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. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d685932e723">Results:</h5> <p id="P3">We identified a <i>de novo</i> novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in <i>ABCC8</i> (ATP-binding cassette, subfamily C, member 8) in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in <i>ABCC8</i> and identified 11 additional heterozygous predicted damaging <i>ABCC8</i> variants. <i>ABCC8</i> encodes sulfonylurea receptor 1 (SUR1), a regulatory subunit of the ATP-sensitive potassium channel (K <sub>ATP</sub>). We observed loss of K <sub>ATP</sub> function for all <i>ABCC8</i> variants evaluated, and pharmacological rescue of all channel currents <i>in vitro</i> by the SUR1 activator, diazoxide. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d685932e756">Conclusions:</h5> <p id="P4">Novel and rare missense variants in <i>ABCC8</i> are associated with pulmonary arterial hypertension. Identified <i>ABCC8</i> mutations decreased K <sub>ATP</sub> channel function, which was pharmacologically recovered. </p> </div>

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Molecular background of leak K+ currents: two-pore domain potassium channels.

Péter Enyedi, Gábor Árpád Czirják (2010)

Two-pore domain K(+) (K(2P)) channels give rise to leak (also called background) K(+) currents. The well-known role of background K(+) currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K(2P) channel types) that this primary hyperpolarizing action is not performed passively. The K(2P) channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K(2P) channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K(2P) channel family into the spotlight. In this review, we focus on the physiological roles of K(2P) channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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KATP channels as molecular sensors of cellular metabolism.

Colin Nichols (2006)

In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (K(ATP)) channel activity provides a unique link between cellular energetics and electrical excitability. Over the past ten years, a steady drumbeat of crystallographic and electrophysiological studies has led to detailed structural and kinetic models that define the molecular basis of channel activity. In parallel, the uncovering of disease-causing mutations of K(ATP) has led to an explanation of the molecular basis of disease and, in turn, to a better understanding of the structural basis of channel function.

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An epidemiological study of pulmonary arterial hypertension.

A J Peacock, N F Murphy, J J V Mcmurray … (2007)

All hospitalisations for pulmonary arterial hypertension (PAH) in the Scottish population were examined to determine the epidemiological features of PAH. These data were compared with expert data from the Scottish Pulmonary Vascular Unit (SPVU). Using the linked Scottish Morbidity Record scheme, data from all adults aged 16-65 yrs admitted with PAH (idiopathic PAH, pulmonary hypertension associated with congenital heart abnormalities and pulmonary hypertension associated with connective tissue disorders) during the period 1986-2001 were identified. These data were compared with the most recent data in the SPVU database (2005). Overall, 374 Scottish males and females aged 16-65 yrs were hospitalised with incident PAH during 1986-2001. The annual incidence of PAH was 7.1 cases per million population. On December 31, 2002, there were 165 surviving cases, giving a prevalence of PAH of 52 cases per million population. Data from the SPVU were available for 1997-2006. In 2005, the last year with a complete data set, the incidence of PAH was 7.6 cases per million population and the corresponding prevalence was 26 cases per million population. Hospitalisation data from the Scottish Morbidity Record scheme gave higher prevalences of pulmonary arterial hypertension than data from the expert centres (Scotland and France). The hospitalisation data may overestimate the true frequency of pulmonary arterial hypertension in the population, but it is also possible that the expert centres underestimate the true frequency.

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Author and article information

Journal

Title: Circulation: Genomic and Precision Medicine

Abbreviated Title: Circ Genom Precis Med.

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 2574-8300

ISSN (Electronic): 2574-8300

Publication date Created: October 2018

Publication date (Print): October 2018

Volume: 11

Issue: 10

Affiliations

[1 ]Department of Pharmacology, College of Physicians and Surgeons (M.S.B., K.J.S., R.S.K.), Columbia University, New York, NY.

[2 ]Department of Pediatrics, College of Physicians and Surgeons (L.M., N.Z., U.K., E.B.R., W.K.C.), Columbia University, New York, NY.

[3 ]Department of Systems Biology (N.Z., H.Q., Y.S.), Columbia University, New York, NY.

[4 ]Department of Applied Physics and Applied Mathematics (H.Q., Y.S.), Columbia University, New York, NY.

[5 ]Department 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.

[6 ]Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc, Tarrytown, NY (C.G.-J., F.E.D., J.D.O., J.G.R., A.R.S., A.B.).

[7 ]Department 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.

[8 ]VU University Medical Center, Amsterdam, the Netherlands (H.J.B., A.C.H., A.V.N.).

[9 ]Golden Jubilee National Hospital, Glasgow, Scotland (C.C., A.J.P.).

[10 ]Royal Free Hospital, London, England (G.C.).

[11 ]Newcastle University (P.A.C.) and Newcastle upon Tyne Hospitals National Health Service Foundation Trust (P.A.C.), United Kingdom.

[12 ]Dépat 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.

[13 ]National Heart and Lung Institute, Imperial College London, United Kingdom (J.S.R.G., S.J.W.).

[14 ]AP-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.).

[15 ]Sheffield Clinical Research Facility, Royal Hallamshire, Sheffield, United Kingdom (D.G.K.).

[16 ]Department of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom (A.L.).

[17 ]Royal United Bath Hospitals, Bath, United Kingdom (R.V.M.R., J.S.).

[18 ]Papworth Hospital, Cambridge, United Kingdom (J.P.-Z., M.T.).

[19 ]Division of Genetics and Molecular Medicine, King’s College London, London, England (R.C.T.).

[20 ]Department of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom (J.W., M.R.W.).

[21 ]Royal Brompton Hospital, London, United Kingdom (S.J.W.).

[22 ]Department of Hematology (S.G.), Addenbrookes Hospital, University of Cambridge, United Kingdom.

Article

DOI: 10.1161/CIRCGEN.118.002087

PMC ID: 6206877

PubMed ID: 30354297

SO-VID: 6abd0484-3f16-4df5-9f64-3180d81a1edc

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Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension

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Most cited references 30

Molecular background of leak K+ currents: two-pore domain potassium channels.

KATP channels as molecular sensors of cellular metabolism.

An epidemiological study of pulmonary arterial hypertension.

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Most referenced authors 677