Zm. Deng et al., Familial primary pulmonary hypertension (gene PPH1) is caused by mutationsin the bone morphogenetic protein receptor-II gene, AM J HU GEN, 67(3), 2000, pp. 737-744
Citations number
37
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
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.