RT Journal Article
SR Electronic
T1 Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 741
OP 745
DO 10.1136/jmg.37.10.741
VO 37
IS 10
A1 Jennifer R Thomson
A1 Rajiv D Machado
A1 Michael W Pauciulo
A1 Neil V Morgan
A1 Marc Humbert
A1 Greg C Elliott
A1 Ken Ward
A1 Magdi Yacoub
A1 Ghada Mikhail
A1 Paula Rogers
A1 John Newman
A1 Lisa Wheeler
A1 Timothy Higenbottam
A1 J Simon R Gibbs
A1 Jim Egan
A1 Agnes Crozier
A1 Andrew Peacock
A1 Robert Allcock
A1 Paul Corris
A1 James E Loyd
A1 Richard C Trembath
A1 William C Nichols
YR 2000
UL http://jmg.bmj.com/content/37/10/741.abstract
AB BACKGROUND Primary pulmonary hypertension (PPH), resulting from occlusion of small pulmonary arteries, is a devastating condition. Mutations of the bone morphogenetic protein receptor type II gene (BMPR2), a component of the transforming growth factor beta (TGF-β) family which plays a key role in cell growth, have recently been identified as causing familial PPH. We have searched for BMPR2 gene mutations in sporadic PPH patients to determine whether the same genetic defect underlies the more common form of the disorder. METHODS We investigated 50 unrelated patients, with a clinical diagnosis of PPH and no identifiable family history of pulmonary hypertension, by direct sequencing of the entire coding region and intron/exon boundaries of the BMPR2 gene. DNA from available parent pairs (n=5) was used to assess the occurrence of spontaneous (de novo) mutations contributing to sporadic PPH. RESULTS We found a total of 11 different heterozygous germline mutations of theBMPR2 gene in 13 of the 50 PPH patients studied, including missense (n=3), nonsense (n=3), and frameshift (n=5) mutations each predicted to alter the cell signalling response to specific ligands. Parental analysis showed three occurrences of paternal transmission and two of de novo mutation of theBMPR2 gene in sporadic PPH. CONCLUSION The sporadic form of PPH is associated with germline mutations of the gene encoding the receptor protein BMPR-II in at least 26% of cases. A molecular classification of PPH, based upon the presence or absence ofBMPR2 mutations, has important implications for patient management and screening of relatives.