Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

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Heterozygous germline mutations ofBMPR2contribute 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, namelySMAD1,SMAD4,SMAD5, andSMAD9, were screened by direct sequencing for gene defects. Four variants were identified inSMADs 1, 4, and9among 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 inSMAD4resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role ofBMPR2mutation in the pathogenesis of PAH and indicate that variation within theSMADfamily represents an infrequent cause of the disease. 32:1385–1389, 2011. ©2011 Wiley Periodicals, Inc.

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