Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Md. Talat Nasim, Takeshi Ogo, Mohammad Ahmed, Rebecca Randall, Hasnin M. Chowdhury, Katie M. Snape, Teisha Y. Bradshaw, Laura Southgate, Grace J. Lee, Ian Jackson, Graham M. Lord, J. Simon R. Gibbs, Martin R. Wilkins, Keiko Ohta-Ogo, Kazufumi Nakamura, Barbara Girerd, Florence Coulet, Florent Soubrier, Marc Humbert, Nicholas W. MorrellRichard C. Trembath, Rajiv D. Machado

Research output: Contribution to journalArticlepeer-review

134 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1385-1389
Number of pages5
JournalHuman Mutation
Issue number12
Publication statusPublished - Dec 2011


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