A novel channelopathy in pulmonary arterial hypertension.
A novel channelopathy in pulmonary arterial hypertension.
复制标题
DOI：
10.1056/nejmoa1211097
复制
发表时间：
2013-07-25
期刊：
影响因子：
--
通讯作者：
Chung WK
中科院分区：
文献类型：
--
作者：
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
肺动脉高压是一种致死率高的严重疾病。家族性肺动脉高压常以常染色体显性遗传为特征，部分家族性肺动脉高压遗传原因不明。我们研究了一个家族，其中多名成员患有肺动脉高压，而已知与该疾病相关的任何基因（包括BMPR 2，ALK 1，ENG，SMAD 9和CAV 1）均无可识别的突变。用全外显子组测序研究了三个家族成员。对其他家族性或特发性肺动脉高压患者进行全外显子组测序鉴定的基因突变筛查。所有变体在COS-7细胞中表达，并通过膜片钳分析研究通道功能。我们在KCNK 3（编码钾通道亚家族K的基因，成员3）中发现了一个新的杂合错义突变体c.608 G→A（G203 D），该突变体是该家族中的致病候选基因。在92名不相关的家族性肺动脉高压患者和230名特发性肺动脉高压患者中独立发现了KCNK 3中的另外5种杂合错义变体。我们使用计算机生物信息学工具来预测所有六种新变异都将是有害的。通道的电生理学研究表明，所有这些错义突变导致功能丧失，并且通过应用磷脂酶抑制剂ONO-RS-082来补救钾通道电流的减少。我们的研究确定了一个新的基因，KCNK 3，与家族性和特发性肺动脉高压的关联。该基因的突变导致钾通道电流降低，通过药理学操作成功补救。（由美国国立卫生研究院资助。
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.)