Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension
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Published version
Embargoed until: 5555-01-01
Reason: Publisher embargo
Embargoed until: 5555-01-01
Reason: Publisher embargo
Volume
32
Pagination
1385 - 1389
DOI
10.1002/humu.21605
Journal
HUMAN MUTATION
Issue
ISSN
1059-7794
Metadata
Show full item recordAbstract
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.