Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Nasim, Md Talat and Ogo, Takeshi and Ahmed, Mohammad and Randall, Rebecca and Chowdhury, Hasnin M. and Snape, Katie M. and Bradshaw, Teisha Y. and Southgate, Laura and Lee, Grace J. and Jackson, Ian and Lord, Graham M. and Gibbs, J. Simon R. and Wilkins, Martin R. and Ohta-Ogo, Keiko and Nakamura, Kazufumi and Girerd, Barbara and Coulet, Florence and Soubrier, Florent and Humbert, Marc and Morrell, Nicholas W. and Trembath, Richard C. and Machado, Rajiv D. (2011) Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Human mutation, 32 (12). pp. 1385-1389. ISSN 1059-7794

Documents
Machado_HMut2011b.pdf
[img]
[Download]
[img] PDF
Machado_HMut2011b.pdf - Whole Document
Restricted to Repository staff only

376Kb

Abstract

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.

Item Type:Article
Additional Information: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.
Keywords:Pulmonary arterial hypertension, BMP pathway, SMAD genes
Subjects:C Biological Sciences > C440 Molecular Genetics
Divisions:College of Science > School of Life Sciences
ID Code:6310
Deposited By: Rajiv Machado
Deposited On:11 Oct 2012 06:22
Last Modified:13 Mar 2013 09:14

Repository Staff Only: item control page