title: Idiopathic pulmonary hypertension: what did we learn from genes?
abstract: Pulmonary arterial hypertension (PAH) is an uncommon disorder. PAH can be idiopathic, associated with other conditions or clustered in families. Indeed, at least 6% of individuals diagnosed with so-called "primary" pulmonary hypertension have a family history of the disorder. Familial PAH segregates as an autosomal dominant trait but with markedly reduced penetrance. Defects within bone morphogenetic protein receptor type II gene (BMPR2), coding for a type II receptor member of the transforming growth factor beta (TGF-beta) family, have been shown to underlie familial PAH. Germline BMPR2 mutations have been detected in at least 60% of the families studied to date. Disease-associated mutations are predicted to interrupt the BMP-mediated signalling pathway predisposing to proliferation of cells within small pulmonary arteries. 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 idiopathic PAH as well as anorexigen-associated PAH turn out to have an inherited basis, as demonstrated by detection of germline BMPR2 mutations. Analysis of other genes encoding TGF-beta receptor proteins, led to the demonstration that PAH in association with hereditary hemorrhagic telangiectasia, an autosomal dominant vascular dysplasia, can involve other TGF-beta receptor subtypes. These observations support the hypothesis that mutations in the TGF-beta superfamily may be a trigger for pulmonary vascular remodeling. Nevertheless, PAH pathobiology remains unclear and genomic approaches may identify additional molecular determinants for this disorder.
authors.affiliation: UPRES 2705, Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, Hôpital Antoine-Bèclère, Université Paris-Sud, Clamart, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sztrymf
authors.forename: Azzedine
authors.initials: A
authors.lastname: Yaïci
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.forename: Gerald
authors.initials: G
authors.lastname: Simonneau
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D008297:Male; D009154:Mutation; D010375:Pedigree; D011379:Prognosis; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D018570:Risk Assessment; D012720:Severity of Illness Index
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D052006:Bone Morphogenetic Protein Receptors, Type II