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Published on: January 16, 2013
Genetic aspects of pulmonary arterial hypertension
J H Morse1, Z Deng, J A Knowles
1Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. jhm4@columbia.edu
Insights
Genetic mutations in bone morphogenetic protein receptor II (BMPR2) are linked to pulmonary arterial hypertension (PAH). Further genetic factors likely contribute to PAH development, suggesting a multi-hit model.
Area of Science:
- Cardiovascular Genetics
- Molecular Medicine
Background:
- Pulmonary arterial hypertension (PAH), including primary pulmonary hypertension (PPH), has significant genetic underpinnings.
- Understanding the genetic basis of PPH is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the genetic mutations associated with familial and sporadic primary pulmonary hypertension (PPH).
- To explore the role of bone morphogenetic protein receptor II (BMPR2) and other genes in PAH pathogenesis.
Main Methods:
- Analysis of germline mutations in patients with familial and sporadic PPH.
- In vitro gene expression experiments to elucidate the mechanism of BMPR2 mutations.
- Review of existing literature on genetic factors in PPH and hereditary haemorrhagic telangiectasia (HHT).
Main Results:
- Germline mutations in BMPR2 were identified in patients with familial and sporadic PPH.
- BMPR2 mutations are predicted to disrupt bone morphogenetic protein (BMP) signaling, leading to vascular cell proliferation.
- Mutations in ALK1 were found in some HHT families with PPH features, indicating a role for other TGF-beta pathway genes.
Conclusions:
- BMPR2 mutations are a significant cause of PPH, acting through haploinsufficiency or potentially a dominant-negative mechanism.
- The incomplete penetrance of BMPR2 mutations suggests other genetic and environmental factors contribute to PPH.
- A multi-hit model, involving genetic and environmental factors, is proposed for the clinical development of PPH.
Abstract:
This paper concentrates on the genetic aspects of pulmonary arterial hypertension (PAH), a diagnostically based subclass of pulmonary hypertension that includes primary pulmonary hypertension (PPH). During the past year, patients with familial and sporadic PPH were found to have germline heterozygous missense, nonsense and frameshift mutations in bone morphogenetic protein receptor II (BMPR2). Mutations in BMPR2, a member of the transforming growth factor-beta (TGF-beta) receptor superfamily, are predicted to interrupt the bone morphogenetic protein (BMP) signalling pathway, resulting in proliferation, rather than apoptosis of cells within small arterioles. Mechanistically, haploinsufficiency was found by using in vitro gene expression experiments, but a dominant-negative mechanism has not been excluded. The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified. Mutations in ALK1, a TGF-beta type 1 receptor, previously known to cause type 2 hereditary haemorrhagic telangiectasia (HHT), have also been reported in a few HHT families with clinical and histological features of PPH. The clinical development of PPH, as in neoplasia, appears to require 'two hits' The two hits can be provided either by genetic or environmental factors.
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