James Loyd
Faculty Member
Last active: 2/12/2015

A novel channelopathy in pulmonary arterial hypertension.

Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouët DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass RS, Chung WK
N Engl J Med. 2013 369 (4): 351-361

PMID: 23883380 · PMCID: PMC3792227 · DOI:10.1056/NEJMoa1211097

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 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.

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.)

MeSH Terms (20)

Amino Acid Sequence Channelopathies Chlorobenzoates Cinnamates Exome Familial Primary Pulmonary Hypertension Female Genetic Predisposition to Disease Heterozygote Humans Hypertension, Pulmonary Lung Male Molecular Sequence Data Mutation, Missense Nerve Tissue Proteins ortho-Aminobenzoates Pedigree Potassium Channels, Tandem Pore Domain Sequence Analysis, DNA

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