Humbert M, Trembath R C
UPRES 2705, Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, Hĵpital Antoine-Béclère, Université Paris-Sud, Clamart.
Eur Respir J. 2002 Sep;20(3):741-9. doi: 10.1183/09031936.02.02702002.
Primary pulmonary hypertension has been described as either sporadic or clustered in families. Familial primary pulmonary hypertension segregates as an autosomal dominant trait with markedly reduced disease gene penetrance. Defects within bone morphogenetic protein receptor type II gene, coding for a receptor member of the transforming growth factor-beta family, underlie familial primary pulmonary hypertension. Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. In addition, a proportion of so-called sporadic primary pulmonary hypertension turns out to have an inherited basis, as demonstrated by germline bone morphogenetic protein receptor type II gene mutations. Analysis of cases in association with hereditary haemorrhagic telangiectasia led to the demonstration that pulmonary arterial hypertension can involve activin-receptor-like kinase 1 mutations, a type I transforming growth factor-beta receptor. These findings emphasise the critical role of the transforming growth factor-beta signalling pathway in pulmonary arterial hypertension. While this achievement has generated extreme interest, the pathobiology of severe pulmonary arterial hypertension remains unclear and genomic approaches to pulmonary hypertension research may identify additional molecular determinants for this disorder. Finally, there is an urgent need to develop relevant guidelines for genetic counselling to assist patients, their relatives and pulmonary vascular specialists to utilise these recent observations.
原发性肺动脉高压被描述为散发性或家族聚集性。家族性原发性肺动脉高压作为常染色体显性性状进行分离，疾病基因的外显率明显降低。编码转化生长因子-β家族受体成员的Ⅱ型骨形态发生蛋白受体基因缺陷是家族性原发性肺动脉高压的基础。多条证据表明，在该疾病的发病机制中，可能还需要其他环境或遗传因素。此外，一部分所谓的散发性原发性肺动脉高压被证明具有遗传基础，生殖系Ⅱ型骨形态发生蛋白受体基因突变就证明了这一点。对与遗传性出血性毛细血管扩张症相关病例的分析表明，肺动脉高压可能涉及激活素受体样激酶1突变，这是一种Ⅰ型转化生长因子-β受体。这些发现强调了转化生长因子-β信号通路在肺动脉高压中的关键作用。尽管这一成果引起了极大关注，但严重肺动脉高压的病理生物学仍不清楚，肺动脉高压研究的基因组方法可能会确定该疾病的其他分子决定因素。最后，迫切需要制定相关的遗传咨询指南，以帮助患者、他们的亲属和肺血管专家利用这些最新观察结果。
