Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene
Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene
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DOI：
10.1086/303059
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发表时间：
2000-09-01
影响因子：
9.8
通讯作者：
Knowles, JA
中科院分区：
文献类型：
--
作者：
Deng, ZM;Morse, JH;Knowles, JA
家族性原发性肺动脉高压是一种罕见的常染色体显性遗传疾病，其染色体畸变率降低，并已定位于染色体2 q33（PPH 1位点）上的一个3-cM区域。该表型的特征是肺小动脉中增殖内皮细胞的单克隆丛状病变。这些病变导致肺动脉压升高、右心室衰竭和死亡。虽然原发性肺动脉高压是罕见的，但继发于已知病因的病例更为常见，包括与食欲抑制药物有关的病例，包括芬氟拉明。我们使用27个微卫星标记对35个患有该疾病的多重家族进行了基因分型;我们构建了疾病单倍型;我们使用TRANSMIT程序寻找了家族间单倍型共享的证据。提示证据的共享观察标记GGAA 19e 07和D2 S307，和三个附近的候选基因进行了检查，通过变性高效液相色谱对来自19个家庭的个人。这些基因之一（BMPR 2），它编码骨形态发生蛋白受体II型，被发现含有五个突变，预测蛋白质产物的过早终止和两个错义突变。在196条对照染色体中未观察到这些突变。这些发现表明，骨形态发生蛋白信号通路在原发性肺动脉高压患者中是有缺陷的，并可能涉及非家族性疾病的途径。
Familial primary pulmonary hypertension is a rare autosomal dominant disorder that has reduced penetrance and that has been mapped to a 3-cM region on chromosome 2q33 (locus PPH1). The phenotype is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles. These lesions lead to elevated pulmonary-artery pressures, right-ventricular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs, including phentermine-fenfluramine. We genotyped 35 multiplex families with the disorder, using 27 microsatellite markers; we constructed disease haplotypes; and we looked for evidence of haplotype sharing across families, using the program TRANSMIT. Suggestive evidence of sharing was observed with markers GGAA19e07 and D2S307, and three nearby candidate genes were examined by denaturing high-performance liquid chromatography on individuals from 19 families. One of these genes (BMPR2), which encodes bone morphogenetic protein receptor type II, was found to contain five mutations that predict premature termination of the protein product and two missense mutations. These mutations were not observed in 196 control chromosomes. These findings indicate that the bone morphogenetic protein-signaling pathway is defective in patients with primary pulmonary hypertension and may implicate the pathway in the nonfamilial forms of the disease.