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family
a Division of
Medical Genetics, Departments of Medicine and Genetics, University of
Leicester, UK, b Division of Human
Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA, c Service de Pneumologie et Reanimation
Respiratoire, Hopital Antoine Beclere, Clamart, France, d LDS
Hospital and the University of Utah, Salt Lake City, Utah 84143, USA, e Department of Human Genetics
and the Eccles Institute of Human Genetics, University of Utah, Salt
Lake City, Utah 84132, USA, f National Heart & Lung Institute, Royal Brompton
& Harefield Hospitals, Harefield, Middlesex, UK, g Vanderbilt
University Medical Center, Nashville, Tennessee 37232, USA, h Department of Respiratory Medicine, Royal
Hallamshire Hospital, Sheffield, UK, i National Heart & Lung
Institute, Imperial College of Science, Technology & Medicine,
Department of Cardiology, Charing Cross Hospital, London, UK, j Department of Respiratory
Medicine, Wythenshawe Hospital, Manchester, UK, k Scottish Pulmonary Vascular Unit,
Western General Hospital, Glasgow, UK, l William Leech Centre for Lung
Research, Royal Freeman Hospital, Newcastle upon Tyne, UK
Correspondence to: Professor Trembath, rtrembat{at}hgmp.mrc.ac.uk
Revised version received 21 July 2000;
Accepted for publication 28 July 2000
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-
) 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.
METHODSWe 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.
RESULTSWe found a total of 11 different heterozygous germline mutations of the
BMPR2 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 the
BMPR2 gene in sporadic PPH.
CONCLUSIONThe 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 of
BMPR2 mutations, has important implications for patient management and screening of relatives.
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
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|
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|
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|
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|
 |
|
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|
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 R Koehler, E Grunig, M W Pauciulo, M M Hoeper, H Olschewski, H Wilkens, M Halank, J Winkler, R Ewert, H Bremer, et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension J. Med. Genet., December 1, 2004; 41(12): e127 - e127. [Full Text] [PDF]
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