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N Engl J Med. 2013 Jul 25;369(4):351-361. doi: 10.1056/NEJMoa1211097.

A novel channelopathy in pulmonary arterial hypertension.

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Departments of Pediatrics (L.M., E.B.R., W.K.C.), Pharmacology (D.R.-C., K.S.S., R.S.K.), and Pathology (A.B.), Columbia University Medical Center, New York; the Departments of Pediatrics (E.D.A.) and Medicine (J.E.L.), Vanderbilt University Medical Center, Nashville; the Genetics Department, Hospital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie (UPMC) Unité Mixte de Recherche en Santé (UMRS) 956, Institute of Cardiometabolism and Nutrition (ICAN) (M.E., F.S.); and INSERM-UPMC UMRS 937, ICAN (M.G., D.-A.T.) - all in Paris; and APHP, Département Hospitalo-Universitaire Thorax Innovation (DHU TORINO), Service de Pneumologie, Hôpital Bicêtre; Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique (LERMIT); and INSERM UMRS 999 - all in Le Kremlin-Bicêtre, France (B.G., D.M., M.H.).
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Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes.


We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis.


We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082.


Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)

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