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.

Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene

“…Shortly after the FPPH locus had been announced, plexiform lesions in PPH were characterized to represent a tumour-like proliferation of a monoclonal population of endothelial cells, indicating that the endothelial cells arose from a selective growth of a single cell, whereas, in secondary PH, endothelial cells in plexiform lesions were polyclonal [3,4]. This finding in turn pointed towards mutational events, such as involving activation of growth-inducing kinase receptors or loss of tumour suppressor genes, as being responsible for the clonal expansion of endothelial cells in PPH [5].Recently, germline mutations in the bone morphogenetic protein receptor II (BMPR-II) (coded within the 2q32-33 region of the PPH1 gene site) were identified in a cohort of patients with FPPH [6,7] (fig. 1) and somatic losses of nucleotides in short stretches of repetitive mono-or dinucleotide sequences of the transforming growth factor-b receptor II (TGF-b RII) and Bax genes were found in endothelial cells in PPH, but not in secondary PH [9].…”

“…Recently, germline mutations in the bone morphogenetic protein receptor II (BMPR-II) (coded within the 2q32-33 region of the PPH1 gene site) were identified in a cohort of patients with FPPH [6,7] ( fig. 1) and somatic losses of nucleotides in short stretches of repetitive mono-or dinucleotide sequences of the transforming growth factor-b receptor II (TGF-b RII) and Bax genes were found in endothelial cells in PPH, but not in secondary PH [9].…”

“…Two groups almost simultaneously reported that BMP-RII mutations occur in a cohort of patients with FPPH [6,7]. BMPR-II mutations were identified in nine of 19 families (47%) in the first study and in seven of eight kindreds with FPPH reported in the second study.…”

Pulmonary Arterial Hypertension: Insights from Genetic Studies

“…E-mail: jim.loyd@vanderbilt.edu identify BMPR2 as the responsible gene in the year 2000 (11). Simultaneous identical progress was contributed independently by Morse and colleagues (12) at Columbia Presbyterian (New York, NY), who also collected a large FPAH cohort and linked FPAH to 2q32 in 1997, then discovered mutations in BMPR2 are responsible for FPAH in 2000 (13).…”

Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertension

“…2). Nevertheless, the discovery of a loss-of-function mutation in bone morphogenetic receptor II (BMPR2), a member of the TGF-β superfamily, in 20 to 30% of patients with idiopathic PAH (IPAH) and 60% of patients with familial PAH immediately paved the way for elucidating the pathobiology of the disease 6,7…”