Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

Yan-Jie Li; Juan Wang; Willy G Ye; Xing-Yuan Liu; Li Li; Xing-Biao Qiu; Honghong Chen; Ying-Jia Xu; Yi-Qing Yang; Donglin Bai; Ri-Tai Huang

doi:10.3390/biology12030346

Discovery of GJC1 (Cx45) as a New Gene Underlying Congenital Heart Disease and Arrhythmias

Biology (Basel). 2023 Feb 21;12(3):346. doi: 10.3390/biology12030346.

Authors

Yan-Jie Li^{1

2}, Juan Wang³, Willy G Ye⁴, Xing-Yuan Liu⁵, Li Li⁶, Xing-Biao Qiu¹, Honghong Chen⁴, Ying-Jia Xu⁷, Yi-Qing Yang^{7

8

9}, Donglin Bai⁴, Ri-Tai Huang¹⁰

Affiliations

¹ Department of Cardiology, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
² Department of Cardiology, Xuhui District Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200030, China.
³ Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
⁴ Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
⁵ Department of Pediatrics, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
⁶ Key Laboratory of Arrhythmias, Ministry of Education of China, School of Medicine, Tongji University, Shanghai 200092, China.
⁷ Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
⁸ Cardiovascular Research Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
⁹ Central Laboratory, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
¹⁰ Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

Abstract

As the most prevalent type of birth malformation, congenital heart disease (CHD) gives rise to substantial mortality and morbidity as well as a socioeconomic burden. Although aggregating investigations highlight the genetic basis for CHD, the genetic determinants underpinning CHD remain largely obscure. In this research, a Chinese family suffering from autosomal dominant CHD (atrial septal defect) and arrhythmias was enrolled. A genome-wide genotyping with microsatellite markers followed by linkage assay as well as sequencing analysis was conducted. The functional effects of the discovered genetic mutation were characterized by dual patch-clamp electrophysiological recordings in N2A cells and propidium iodide uptake assays in HeLa cells. As a result, a novel genetic locus for CHD and arrhythmias was located on chromosome 17q21.31-q21.33, a 4.82-cM (5.12 Mb) region between two markers of D17S1861 and D17S1795. Sequencing assays of the genes at the mapped locus unveiled a novel heterozygous mutation in the GJC1 gene coding for connexin 45 (Cx45), NM_005497.4:c.550A>G;p.R184G, which was in co-segregation with the disease in the whole family and was not observed in 516 unrelated healthy individuals or gnomAD. Electrophysiological analyses revealed that the mutation significantly diminished the coupling conductance in homomeric cell pairs (R184G/R184G) and in cell pairs expressing either R184G/Cx45 or R184G/Cx43. Propidium iodide uptake experiments demonstrated that the Cx45 R184G mutation did not increase the Cx45 hemichannel function. This investigation locates a new genetic locus linked to CHD and arrhythmias on chromosome 17q21.31-q21.33 and indicates GJC1 as a novel gene predisposing to CHD and arrhythmias, implying clinical implications for prognostic risk assessment and personalized management of patients affected with CHD and arrhythmias.

Keywords: GJC1; arrhythmia; atrioventricular block; cardiac septal defect; congenital heart disease; gap junction channel; molecular genetics; patch clamp electrophysiology.

Abstract

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