The pathogenesis of primary pulmonary arterial hypertension (PAH) is unknown. The main goal of this project continues to be the identification of genes that cause PAH and how these genes contribute to the pathophysiology of the disease and its clinical subsets. The familial form of primary pulmonary hypertension (FPPH), inherited as an autosomal dominant disease with incomplete penetrance, was known to have a gene, PPH1 located on chromosome 2q32,33. After narrowing this large locus, our studies found mutations of bone morphogenetic protein receptor 2 (BMPR2) caused disease in 9 of 21 FPPH families. Others found BMPR2 mutations in 26% of sporadic PPH. BMPR2 mutations were also found 9% of fenfluramine appetite-associated PAH whereas no mutations were found in PAH patients with HIV-infection or with scleroderma spectrum of disease. BMPR2 mutations remain to be determined in large PAH cohorts of children and adults with anatomically large congenital pulmonary to systemic communications and with sporadic PPH. Our clinical resources include 100 FPPH families and 5 hereditary hemorrhagic telangiectasia (HHT1) families, four have mutations in activin-like receptor 1 (ALK-1), another gene associated with PPH. The identification of BMPR2 gene, a member of the TGF-B superfamly has focused the BMP/TGF-B signaling pathway for new explorations into the pathogenesis of PPH. Our newer aims will investigate the mechanism by which BMPR2 mutations cause disease, identify genetic mutations that cause disease in the 50% of FPPH cases that do not contain mutations in the exons of BMPR2, and identify DNA variations that alter the penetrance of BMPR2 mutations. We are most interested in the long C-terminal tail of BMPR2, which is unique in the TGF-B superfamily. Hopefully, these aims and the large available clinical material should provide pathophysiological information on the functional relevance of BMPR2 mutations, provide an in vitro method of BMPR2 evaluation, and provide the identification of additional risk factors and genes required for disease penetrance. Longitudinal follow of the FPPH and sporadic cases and of the HHT families should give information on the natural history of disease. The results could also define further avenues for therapeutic interventions and potentially provide in vitro models for drug testing. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060056-08
Application #
7146703
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Gan, Weiniu
Project Start
1999-08-23
Project End
2008-11-30
Budget Start
2006-12-01
Budget End
2008-11-30
Support Year
8
Fiscal Year
2007
Total Cost
$407,251
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Okur, Volkan; Nees, Shannon; Chung, Wendy K et al. (2018) Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J Med Genet A 176:1773-1777
Bohnen, Michael S; Ma, Lijiang; Zhu, Na et al. (2018) Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med 11:e002087
Zhu, Na; Welch, Carrie L; Wang, Jiayao et al. (2018) Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. Genome Med 10:56
Zhu, Na; Gonzaga-Jauregui, Claudia; Welch, Carrie L et al. (2018) Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. Circ Genom Precis Med 11:e001887
Ma, Lijiang; Chung, Wendy K (2017) The role of genetics in pulmonary arterial hypertension. J Pathol 241:273-280
Evans, Jonathan D W; Girerd, Barbara; Montani, David et al. (2016) BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med 4:129-37
Machado, Rajiv D; Southgate, Laura; Eichstaedt, Christina A et al. (2015) Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat 36:1113-27
Ma, Lijiang; Chung, Wendy K (2014) The genetic basis of pulmonary arterial hypertension. Hum Genet 133:471-9
Best, D Hunter; Sumner, Kelli L; Austin, Eric D et al. (2014) EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 145:231-236
Germain, Marine; Eyries, Mélanie; Montani, David et al. (2013) Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 45:518-21

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