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Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models

BACKGROUND: GJA1 gene encodes a gap junction protein known as connexin 43 (Cx43). Cx43 is abundantly expressed in the ventricular myocardium and in cardiac neural crest cells. Cx43 is proposed to play an important role in human congenital heart disease, as GJA1 knock-out mice die neonatally from out...

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Autores principales: Huang, Guo-Ying, Xie, Li-Jian, Linask, Kaari L., Zhang, Chen, Zhao, Xiao-Qing, Yang, Yi, Zhou, Guo-Min, Wu, Ying-Jie, Marquez-Rosado, Lucrecia, McElhinney, Doff B., Goldmuntz, Elizabeth, Liu, Chengyu, Lampe, Paul D., Chatterjee, Bishwanath, Lo, Cecilia W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Medknow Publications Pvt Ltd 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224440/
https://www.ncbi.nlm.nih.gov/pubmed/22135478
http://dx.doi.org/10.4103/0975-3583.89804
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author Huang, Guo-Ying
Xie, Li-Jian
Linask, Kaari L.
Zhang, Chen
Zhao, Xiao-Qing
Yang, Yi
Zhou, Guo-Min
Wu, Ying-Jie
Marquez-Rosado, Lucrecia
McElhinney, Doff B.
Goldmuntz, Elizabeth
Liu, Chengyu
Lampe, Paul D.
Chatterjee, Bishwanath
Lo, Cecilia W.
author_facet Huang, Guo-Ying
Xie, Li-Jian
Linask, Kaari L.
Zhang, Chen
Zhao, Xiao-Qing
Yang, Yi
Zhou, Guo-Min
Wu, Ying-Jie
Marquez-Rosado, Lucrecia
McElhinney, Doff B.
Goldmuntz, Elizabeth
Liu, Chengyu
Lampe, Paul D.
Chatterjee, Bishwanath
Lo, Cecilia W.
author_sort Huang, Guo-Ying
collection PubMed
description BACKGROUND: GJA1 gene encodes a gap junction protein known as connexin 43 (Cx43). Cx43 is abundantly expressed in the ventricular myocardium and in cardiac neural crest cells. Cx43 is proposed to play an important role in human congenital heart disease, as GJA1 knock-out mice die neonatally from outflow tract obstruction. In addition, patients with visceroatrial heterotaxia or hypoplastic left heart syndrome were reported to have point mutations in GJA1 at residues that affect protein kinase phosphorylation and gating of the gap junction channel. However, as these clinical findings were not replicated in subsequent studies, the question remains about the contribution of GJA1 mutations in human congenital heart disease (CHD). MATERIALS AND METHODS: We analyzed the GJA1 coding sequence in 300 patients with CHD from two clinical centers, focusing on outflow tract anomalies. This included 152 with Tetralogy of Fallot from over 200 patients exhibiting outflow tract anomalies, as well as other structural heart defects including atrioventricular septal defects and other valvar anomalies. Our sequencing analysis revealed only two silent nucleotide substitutions in 8 patients. To further assess the possible role of Cx43 in CHD, we also generated two knock-in mouse models with point mutations at serine residues subject to protein kinase C or casein kinase phosphorylation, sites that are known to regulate gating and trafficking of Cx43, respectively. RESULTS: Both heterozygous and homozygous knock-in mice were long term viable and did not exhibit overt CHD. CONCLUSION: The combined clinical and knock-in mouse mutant studies indicate GJA1 mutation is not likely a major contributor to CHD, especially those involving outflow tract anomalies.
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spelling pubmed-32244402011-12-01 Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models Huang, Guo-Ying Xie, Li-Jian Linask, Kaari L. Zhang, Chen Zhao, Xiao-Qing Yang, Yi Zhou, Guo-Min Wu, Ying-Jie Marquez-Rosado, Lucrecia McElhinney, Doff B. Goldmuntz, Elizabeth Liu, Chengyu Lampe, Paul D. Chatterjee, Bishwanath Lo, Cecilia W. J Cardiovasc Dis Res Original Article BACKGROUND: GJA1 gene encodes a gap junction protein known as connexin 43 (Cx43). Cx43 is abundantly expressed in the ventricular myocardium and in cardiac neural crest cells. Cx43 is proposed to play an important role in human congenital heart disease, as GJA1 knock-out mice die neonatally from outflow tract obstruction. In addition, patients with visceroatrial heterotaxia or hypoplastic left heart syndrome were reported to have point mutations in GJA1 at residues that affect protein kinase phosphorylation and gating of the gap junction channel. However, as these clinical findings were not replicated in subsequent studies, the question remains about the contribution of GJA1 mutations in human congenital heart disease (CHD). MATERIALS AND METHODS: We analyzed the GJA1 coding sequence in 300 patients with CHD from two clinical centers, focusing on outflow tract anomalies. This included 152 with Tetralogy of Fallot from over 200 patients exhibiting outflow tract anomalies, as well as other structural heart defects including atrioventricular septal defects and other valvar anomalies. Our sequencing analysis revealed only two silent nucleotide substitutions in 8 patients. To further assess the possible role of Cx43 in CHD, we also generated two knock-in mouse models with point mutations at serine residues subject to protein kinase C or casein kinase phosphorylation, sites that are known to regulate gating and trafficking of Cx43, respectively. RESULTS: Both heterozygous and homozygous knock-in mice were long term viable and did not exhibit overt CHD. CONCLUSION: The combined clinical and knock-in mouse mutant studies indicate GJA1 mutation is not likely a major contributor to CHD, especially those involving outflow tract anomalies. Medknow Publications Pvt Ltd 2011 /pmc/articles/PMC3224440/ /pubmed/22135478 http://dx.doi.org/10.4103/0975-3583.89804 Text en Copyright: © Journal of Cardiovascular Disease Research http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Huang, Guo-Ying
Xie, Li-Jian
Linask, Kaari L.
Zhang, Chen
Zhao, Xiao-Qing
Yang, Yi
Zhou, Guo-Min
Wu, Ying-Jie
Marquez-Rosado, Lucrecia
McElhinney, Doff B.
Goldmuntz, Elizabeth
Liu, Chengyu
Lampe, Paul D.
Chatterjee, Bishwanath
Lo, Cecilia W.
Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title_full Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title_fullStr Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title_full_unstemmed Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title_short Evaluating the role of connexin43 in congenital heart disease: Screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
title_sort evaluating the role of connexin43 in congenital heart disease: screening for mutations in patients with outflow tract anomalies and the analysis of knock-in mouse models
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224440/
https://www.ncbi.nlm.nih.gov/pubmed/22135478
http://dx.doi.org/10.4103/0975-3583.89804
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