期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 369, 期 4, 页码 351-361出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1211097
关键词
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资金
- National Institutes of Health [R01 HL060056, P01 HL072058, K23 HL098743, R01 HL 56810]
- Vanderbilt Clinical and Translational Science Awards grant from the National Center for Research Resources [UL1 RR024975]
- National Heart, Lung, and Blood Institute (NHLBI) [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924]
- NHLBI [RC2 HL-102925, RC2 HL-102926]
BACKGROUND 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. METHODS 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. RESULTS We identified a novel heterozygous missense variant c.608 GA (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. CONCLUSIONS 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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