Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene

Abstract

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.

Figure 1

Intron/exon structure of the human BMPR2 gene. Intron and exon sizes are as indicated. Protein start and stop codons are indicated by the horizontal arrow and “TGA,” respectively. Mutations that cause premature termination of BMPR2 are shown as blackened arrows; unblackened arrows denote mutations in Arg491. The transmembrane and kinase domains are encoded by the indicated exons.

Figure 2

Sequence alignment of the type II TGF-β–superfamily receptors surrounding R491 in BMPR-II. The mutation in families PPH001, PPH008, and PPH021 was aligned with all known type II receptors (>50), and 14 of these are displayed. TGFR-II = TGF-β–receptor type II; ActR-II = activin receptor type II; AMHR-II = anti–mullerian hormone type II receptor; DAF-4 = development-regulatory growth factor type IV; XSTK3 = Xenopus activin receptor.