A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance.MethodsTo elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls.ResultsA burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10−8). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population.ConclusionsThe variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-017-0400-z) contains supplementary material, which is available to authorized users.

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“…Moreover, in vivo pharmacological activation with ONO‐RS‐082 of KCNK3 significantly reversed pulmonary hypertension in rats and partially restored the function of some KCNK3 mutants channels . KCNK3 mutations may be associated with certain forms of pulmonary hypertension, and they may cause worsening of the clinical features in homozygous patients . Higasa et al.…”

“…Higasa et al. suggested that rare pathogenic variants in KCNK3 may also increase the risk of familial PA hypertension. Cunningham et al.…”

Genetics of Pulmonary Arterial Hypertension

“…29 While studies of KCNK3 continue, it appears that the frequency of KCNK3 mutations among those without detectable mutations in BMPR2, ALK1, ENG, and CAV1 is higher among PAH families than data presented for CAV1 (3.26% [3 out of 92] of PAH families and 1.32% [3 out of 228] of IPAH cases had detectable KCNK3 mutations), but much lower than BMPR2. [30][31][32] The biologic plausibility of the relevance of KCNK3 mutations to PAH is high. KCNK3 encodes the TASK-1 protein, which is a pH-sensitive potassium channel.…”

Repurposing benzbromarone for pulmonary arterial hypertension: can channelling the past deliver the therapy of the future?

“…Together, increased Ca 2+ influx and reduced K + efflux contribute to membrane depolarisation and a further elevation of [Ca 2+ ] cyt via the opening of voltage-dependent calcium channels (figure 1). More recently, genetic screening of both heritable PAH families and idiopathic PAH (IPAH) patient cohorts enabled the identification of heterozygous loss-of-function mutations in KCNK3, the gene encoding the TASK-1 potassium channel, in both patient populations [6,7]. KCNK3 is decreased in the monocrotaline rat model of PAH and its inhibition was found to induce aberrant pulmonary vascular cell proliferation in control rats [8].…”