Familial and sporadic primary pulmonary hypertension is caused by BMPR2 gene mutations resulting in haploinsufficiency of the bone morphogenetic protein tùype II receptor

Abstract

Primary pulmonary hypertension (PPH) is characterised by pulmonary artery smooth muscle cell hypertrophy, intimal proliferation and in situ thrombus formation. Heterozygous germline mutations of the BMPR2 gene, a member of the TGFbeta cell signalling super family, have been identified in familial PPH. To determine if BMPR2 gene defects predispose to sporadic PPH, we analysed the BMPR2 gene in lymphocytic DNA from 50 patients, with no identifiable family history. We found heterozygous mutations in 16 patients, being similar in type and distribution across the BMPR2 gene as in familial PPH. Of those with detectable mutations, there were 11 females and 5 males, age of onset ranged from 17–43 years and 3 had heart/lung transplants. To assess if spontaneous mutations contribute to sporadic PPH, DNA from 5 parent pairs was analysed, revealing 3 occurrences of paternal transmission and 2 de novo BMPR2 gene mutations. We also report the spectrum of BMPR2 mutations in 32 PPH families. The majority of mutations (58%) are predicted to lead to premature termination codons, suggesting that haploinsufficiency represents the common molecular mechanism in PPH. Furthermore, marked variability for the age of disease onset was observed within and between families. In conclusion, germline mutations of the BMPR2 gene are detected in familial PPH and at least 32% of sporadic PPH patients. There is considerable heterogeneity of BMPR2 mutations and additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype. A molecular classification of PPH, based upon the presence or absence of BMPR2 mutations, has important implications for patient management and screening of relatives. ∗equal contribution