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. Morrell; Richard C. Trembath; Rajiv D. Machado

doi:10.1002/humu.21605

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

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

146 Citations (Scopus)

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. 32:13851389, 2011. (C) 2011 Wiley Periodicals, Inc.

Original language	English
Pages (from-to)	1385-1389
Number of pages	5
Journal	Human Mutation
Volume	32
Issue number	12
DOIs	https://doi.org/10.1002/humu.21605
Publication status	Published - Dec 2011

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Nasim, M. T., Ogo, T., Ahmed, M., Randall, R., Chowdhury, H. M., Snape, K. M., Bradshaw, T. Y., Southgate, L., Lee, G. J., Jackson, I., Lord, G. M., Gibbs, J. S. R., Wilkins, M. R., Ohta-Ogo, K., Nakamura, K., Girerd, B., Coulet, F., Soubrier, F., Humbert, M., ... Machado, R. D. (2011). Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Human Mutation, 32(12), 1385-1389. https://doi.org/10.1002/humu.21605

@article{9cf0d74dcca843808876e48025554d6a,

title = "Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension",

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. 32:13851389, 2011. (C) 2011 Wiley Periodicals, Inc.",

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

year = "2011",

month = dec,

doi = "10.1002/humu.21605",

language = "English",

volume = "32",

pages = "1385--1389",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley",

number = "12",

}

Nasim, MT, Ogo, T, Ahmed, M, Randall, R, Chowdhury, HM, Snape, KM, Bradshaw, TY, Southgate, L , Lee, GJ, Jackson, I, Lord, GM, Gibbs, JSR, Wilkins, MR, Ohta-Ogo, K, Nakamura, K, Girerd, B, Coulet, F, Soubrier, F, Humbert, M, Morrell, NW, Trembath, RC & Machado, RD 2011, 'Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension', Human Mutation, vol. 32, no. 12, pp. 1385-1389. https://doi.org/10.1002/humu.21605

TY - JOUR

T1 - Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

AU - Nasim, Md. Talat

AU - Ogo, Takeshi

AU - Ahmed, Mohammad

AU - Randall, Rebecca

AU - Chowdhury, Hasnin M.

AU - Snape, Katie M.

AU - Bradshaw, Teisha Y.

AU - Southgate, Laura

AU - Lee, Grace J.

AU - Jackson, Ian

AU - Lord, Graham M.

AU - Gibbs, J. Simon R.

AU - Wilkins, Martin R.

AU - Ohta-Ogo, Keiko

AU - Nakamura, Kazufumi

AU - Girerd, Barbara

AU - Coulet, Florence

AU - Soubrier, Florent

AU - Humbert, Marc

AU - Morrell, Nicholas W.

AU - Trembath, Richard C.

AU - Machado, Rajiv D.

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

U2 - 10.1002/humu.21605

DO - 10.1002/humu.21605

M3 - Article

SN - 1059-7794

VL - 32

SP - 1385

EP - 1389

JO - Human Mutation

JF - Human Mutation

IS - 12

ER -

Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension

Abstract

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