E-ISSN 0976-2833 | ISSN 0975-3583
 

Original Article 


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

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo.

Abstract
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.

Key words: congenital heart diseaseConnexin43gap junctionknock-in mouse modeloutflow tractphosphorylations


 
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Pubmed Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. 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. J Cardiovasc. Dis. Res.. 2011; 2(4): 206-212. doi:10.4103/0975-3583.89804


Web Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. 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. http://www.jcdronline.org/?mno=93192 [Access: January 16, 2022]. doi:10.4103/0975-3583.89804


AMA (American Medical Association) Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. 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. J Cardiovasc. Dis. Res.. 2011; 2(4): 206-212. doi:10.4103/0975-3583.89804



Vancouver/ICMJE Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. 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. J Cardiovasc. Dis. Res.. (2011), [cited January 16, 2022]; 2(4): 206-212. doi:10.4103/0975-3583.89804



Harvard Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo (2011) 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. J Cardiovasc. Dis. Res., 2 (4), 206-212. doi:10.4103/0975-3583.89804



Turabian Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. 2011. 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. Journal of Cardiovascular Disease Research, 2 (4), 206-212. doi:10.4103/0975-3583.89804



Chicago Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. "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." Journal of Cardiovascular Disease Research 2 (2011), 206-212. doi:10.4103/0975-3583.89804



MLA (The Modern Language Association) Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo. "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." Journal of Cardiovascular Disease Research 2.4 (2011), 206-212. Print. doi:10.4103/0975-3583.89804



APA (American Psychological Association) Style

Guo-Ying Huang, Li-Jian Xie, Kaari L. Linask, Chen Zhang, Xiao-Qing Zhao, YiYang, Guo-Min Zhou, Ying-Jie Wu, Lucrecia Marquez-Rosado, Doff B. McElhinney,Elizabeth Goldmuntz, Chengyu Liu, Paul D. Lampe, Bishwanath Chatterjee,Cecilia W. Lo (2011) 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. Journal of Cardiovascular Disease Research, 2 (4), 206-212. doi:10.4103/0975-3583.89804





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