期刊
HUMAN MUTATION
卷 32, 期 12, 页码 1385-1389出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.21605
关键词
pulmonary hypertension; BMPR2; SMAD4; transcriptional regulation
资金
- British Heart Foundation [RG/08/006/25302, FS/07/036]
- National Institute for Health Research
- British Heart Foundation [RG/08/002/24718, RG/08/006/25302] Funding Source: researchfish
- Medical Research Council [G1000758B, G1000758] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10379, NF-SI-0508-10212] Funding Source: researchfish
Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease. 32:13851389, 2011. (C) 2011 Wiley Periodicals, Inc.
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