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Comparative Analysis of BMPR2 Gene and Its Mutations in Idiopathic Pulmonary Arterial Hypertension* FREE TO VIEW

Wai P. K. Wong, PhD; James A. Knowles, MD, PhD; Jane H. Morse, MD
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*From the Department of Medicine, Department of Psychiatry, Columbia Genome Center, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY.

Correspondence to: James A. Knowles, MD, PhD, Associate Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons, Columbia Genome Center, New York State Psychiatric Institute, 1051 Riverside Dr, Room 5916, Unit 28, New York, NY 10032; e-mail jak8@columbia.edu

Chest. 2005;128(6_suppl):615S. doi:10.1378/chest.128.6_suppl.615S-a
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Mutations of the gene BMPR2 encoding the protein bone morphogenetic protein receptor type II have been found in the patients with familial and sporadic forms of idiopathic pulmonary arterial hypertension (IPAH). The BMPR2 gene belongs to the transforming growth factor-β receptor protein family, which is a large family of different proteins that regulate normal cell growth. When the gene is mutated or becomes defective, it allows the vascular cells within the small pulmonary arteries to grow unregulated and block the blood vessels.

The predicted protein structure of BMPR2 consists of extracellular ligand binding, transmembrane, kinase, and long cytoplasmic domains. In this study, we performed a comparative sequence analysis of BMPR2 from diverse vertebrates and invertebrates. We found that the protein kinase domain exhibited an overall high degree of conservation (85 to 99% identity in vertebrates), while the extracellular domain and the long cytoplasmic tail with largely unknown function were more divergent. However, within the cytoplasmic tail, we identified several highly conserved regions, including a 44-amino acid proline-glutamic acid-serine-threonine motif, which were likely to represent functional or structural subdomains.

In addition, comparison of human, mouse, and zebra fish BMPR2 exons revealed an increased rate of nonsynonymous nucleotide substitutions in exons 12 and 13, which encoded most of the cytoplasmic tail, compared to the other exons. This finding suggested that the cytoplasmic tail may have evolved under different functional constraints. Furthermore, the distribution of IPAH-associated mutations and neutral polymorphisms suggested that IPAH-associated missense mutations occurred at highly conserved residues while polymorphisms were in regions of lower conservation. Remarkably, almost all of the 20 missense mutations occurred at nucleotides and amino acids that were identical across all species studied. Taken together, these data identified the regions of the BMPR2 gene that may be critical for its normal function.

Abbreviation: IPAH = idiopathic pulmonary arterial hypertension




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