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

Familial primary pulmonary hypertension is a rare autosomal dominant disord er 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 arteriol es. These lesions lead to elevated pulmonary-artery pressures, right-ventri cular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those assoc iated with the appetite-suppressant drugs, including phentermine-fenflurami ne. We genotyped 35 multiplex families with the disorder, using 27 microsat ellite markers; we constructed disease haplotypes; and we looked for eviden ce of haplotype sharing across families, using the program TRANSMIT. Sugges tive evidence of sharing was observed with markers GGAA19e07 and D2S307, an d 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 fou nd to contain five mutations that predict premature termination of the prot ein product and two missense mutations. These mutations were not observed i n 196 control chromosomes. These findings indicate that the bone morphogene tic protein-signaling pathway is defective in patients with primary pulmona ry hypertension and may implicate the pathway in the nonfamilial forms of t he disease.