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Genetics of pulmonary hypertension: from bench to bedside

¹ UPRES 2705, Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine-Béclère, Université Paris-Sud, Clamart. ² Division of Medical Genetics, Depts of Medicine and Genetics, University of Leicester, Leicester, UK

CORRESPONDENCE: M. Humbert, Service de Pneumologie, Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140, Clamart, France. Fax: 33 146303824. E-mail: humbert@ipsc.u-psud.fr

Keywords: activin-receptor-like kinase 1, bone morphogenetic protein receptor type II gene, fenfluramine derivatives, hereditary haemorrhagic telangiectasia, primary pulmonary hypertension, pulmonary arterial hypertension

Received: April 2, 2002
Accepted April 19, 2002

M. Humbert and R.C. Trembath were supported in part by Université Paris-Sud, University of Leicester, MRC (UK), BHF, INSERM and AFM.

Abstract

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-ß 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-ß receptor. These findings emphasise the critical role of the transforming growth factor-ß 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.

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