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首页> 外文期刊>The New England journal of medicine >A novel channelopathy in pulmonary arterial hypertension
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A novel channelopathy in pulmonary arterial hypertension

机译：肺动脉高压中的新型通道病

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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.)
机译：背景：肺动脉高压是一种具有高死亡率的毁灭性疾病。家族性肺动脉高压病例通常以常染色体显性遗传传播和外显率降低为特征，某些家族性病例的遗传原因未知。方法：我们研究了一个家庭，其中多个成员患有肺动脉高压，而与该疾病相关的任何基因（包括BMPR2，ALK1，ENG，SMAD9和CAV1）都没有可识别的突变。用全外显子组测序研究了三个家庭成员。筛选了其他患有家族性或特发性肺动脉高压的患者，寻找通过全外显子组测序鉴定出的基因突变。所有变体均在COS-7细胞中表达，并通过膜片钳分析研究了通道功能。结果：我们在KCNK3（编码钾通道亚家族K的基因，成员3）中鉴定了一个新的杂合错义变体c.608 G→A（G203D）作为该家族中的致病候选基因。在92例家族性肺动脉高压无关患者和230例特发性肺动脉高压患者中，独立鉴定出KCNK3的另外5个杂合错义变异体。我们使用计算机生物信息学工具来预测所有六个新变体均会造成破坏。通道的电生理研究表明，所有这些错义突变均导致功能丧失，并且通过应用磷脂酶抑制剂ONO-RS-082可以弥补钾通道电流的减少。结论：我们的研究确定了一个新基因KCNK3与家族性和特发性肺动脉高压的相关性。该基因的突变产生减少的钾通道电流，这已通过药理学操作成功修复。 （由国立卫生研究院资助。）

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