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BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension
Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperp...
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| Jazyk: | English |
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The American Society of Human Genetics
2001
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| On-line přístup: | https://ncbi.nlm.nih.gov/pmc/articles/PMC1234937/ https://ncbi.nlm.nih.gov/pubmed/11115378 |
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pubmed-12349372006-02-01 BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension Machado, Rajiv D Pauciulo, Michael W. Thomson, Jennifer R. Lane, Kirk B. Morgan, Neil V. Wheeler, Lisa Phillips III, John A. Newman, John Williams, Denise Galiè, Nazzareno Manes, Alessandra McNeil, Keith Yacoub, Magdi Mikhail, Ghada Rogers, Paula Corris, Paul Humbert, Marc Donnai, Dian Martensson, Gunnar Tranebjaerg, Lisbeth Loyd, James E. Trembath, Richard C. Nichols, William C. Am J Hum Genet Articles Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor β (TGF-β) cell–signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype. The American Society of Human Genetics 2001-01 2000-12-12 /pmc/articles/PMC1234937/ /pubmed/11115378 Text en © 2001 by The American Society of Human Genetics. All rights reserved. |
| institution |
US National Library of Medicine |
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PubMed Central |
| language |
English |
| format |
Article |
| topic |
Articles |
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Articles Machado, Rajiv D Pauciulo, Michael W. Thomson, Jennifer R. Lane, Kirk B. Morgan, Neil V. Wheeler, Lisa Phillips III, John A. Newman, John Williams, Denise Galiè, Nazzareno Manes, Alessandra McNeil, Keith Yacoub, Magdi Mikhail, Ghada Rogers, Paula Corris, Paul Humbert, Marc Donnai, Dian Martensson, Gunnar Tranebjaerg, Lisbeth Loyd, James E. Trembath, Richard C. Nichols, William C. BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| description |
Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor β (TGF-β) cell–signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype. |
| author |
Machado, Rajiv D Pauciulo, Michael W. Thomson, Jennifer R. Lane, Kirk B. Morgan, Neil V. Wheeler, Lisa Phillips III, John A. Newman, John Williams, Denise Galiè, Nazzareno Manes, Alessandra McNeil, Keith Yacoub, Magdi Mikhail, Ghada Rogers, Paula Corris, Paul Humbert, Marc Donnai, Dian Martensson, Gunnar Tranebjaerg, Lisbeth Loyd, James E. Trembath, Richard C. Nichols, William C. |
| author_facet |
Machado, Rajiv D Pauciulo, Michael W. Thomson, Jennifer R. Lane, Kirk B. Morgan, Neil V. Wheeler, Lisa Phillips III, John A. Newman, John Williams, Denise Galiè, Nazzareno Manes, Alessandra McNeil, Keith Yacoub, Magdi Mikhail, Ghada Rogers, Paula Corris, Paul Humbert, Marc Donnai, Dian Martensson, Gunnar Tranebjaerg, Lisbeth Loyd, James E. Trembath, Richard C. Nichols, William C. |
| author_sort |
Machado, Rajiv D |
| title |
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| title_short |
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| title_full |
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| title_fullStr |
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| title_full_unstemmed |
BMPR2 Haploinsufficiency as the Inherited Molecular Mechanism for Primary Pulmonary Hypertension |
| title_sort |
bmpr2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension |
| publisher |
The American Society of Human Genetics |
| publisher_facet |
The American Society of Human Genetics |
| publishDate |
2001 |
| url |
https://ncbi.nlm.nih.gov/pmc/articles/PMC1234937/ https://ncbi.nlm.nih.gov/pubmed/11115378 |
| _version_ |
1760283449328926720 |