Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension
Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension
复制标题
DOI：
10.1002/humu.21605
复制
发表时间：
2011-12-01
期刊：
影响因子：
3.9
通讯作者：
Machado, Rajiv D.
中科院分区：
文献类型：
--
作者：
Nasim, Md. Talat;Ogo, Takeshi;Machado, Rajiv D.
BMPR2杂合胚系突变导致家族性肺动脉高压(PAH)。为了进一步探索PAH在个别病例中的遗传基础，我们进行了候选基因分析，以确定潜在的有害变异。骨形态发生蛋白(BMP)途径的成员，即Smad1、Smad4、Smad5和Smad9，通过直接测序筛选基因缺陷。在324例PAH病例的队列中，在SMADS 1、4和9中发现了4个变异，每个病例都没有在大量对照人群中检测到。在已鉴定的三个氨基酸替换中，有两个在体外显示信号活性降低。Smad4中一个假定的剪接位点突变导致剪接效率下降，导致适度的转录损失。这些结果证明了BMPR2突变在PAH发病机制中的作用，并表明SMAD家族内的变异是一种罕见的疾病原因。2011年，32：13851389。(C)2011年威利期刊公司。
Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease. 32:13851389, 2011. (C) 2011 Wiley Periodicals, Inc.