Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family
Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family
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DOI：
10.1136/jmg.37.10.741
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发表时间：
2000-10-01
影响因子：
4
通讯作者：
Nichols, WC
中科院分区：
文献类型：
--
作者：
Thomson, JR;Machado, RD;Nichols, WC
背景-原发性肺动脉高压（PPH），由小肺动脉阻塞引起，是一种毁灭性的疾病。骨形态发生蛋白受体II型基因（BMPR 2）是转化生长因子β（TGF-β）家族的一个组成部分，在细胞生长中起着关键作用，最近已被确定为引起家族性PPH。我们已经搜索了BMPR 2基因突变在散发性PPH患者，以确定是否相同的遗传缺陷的基础上更常见的形式disorder. Methods，我们调查了50个无关的患者，PPH的临床诊断和肺动脉高压的家族史，通过直接测序的整个编码区和内含子/外显子边界的BMPR 2基因。结果-我们在研究的50例PPH患者中的13例中发现了BMPR 2基因的总共11种不同的杂合种系突变，包括错义突变（n=3），无义突变（n = 3），和移码（n=5）突变，每个突变预测改变细胞对特定配体的信号传导应答。父母的分析表明，发生三次父亲的传播和两个从头突变的BMPR 2基因在散发性PPH. Conclusion的散发形式的PPH与生殖系突变的基因编码的受体蛋白BMPR-II在至少26%的情况下。PPH的分子分类，基于BMPR 2突变的存在或不存在，对患者管理和亲属筛查具有重要意义。
Background-Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-beta) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder.Methods-We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH.Results-We found a total of 11 different heterozygous germline mutations of the BMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of the BMPR2 gene in sporadic PPH.Conclusion-The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives.