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

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.

Connexin45 (GJC1) loss-of-function mutation contributes to familial atrial fibrillation and conduction disease.

Background: Atrial fibrillation (AF) represents the most common clinical cardiac arrhythmia and substantially increases the risk of cerebral stroke, heart failure, and death. Although causative genes for AF have been identified, the genetic determinants for AF remain largely unclear.

Objective: This study aimed to investigate the molecular basis of AF in a Chinese kindred.

Junctional delay, frequency, and direction-dependent uncoupling of human heterotypic Cx45/Cx43 gap junction channels.

Gap junction (GJ) channels form low resistance passages between cardiomyocytes and play a role in the rapid propagation of action potentials in the heart. A GJ channel is formed by two properly docked hemichannels and each hemichannel is a hexamer of connexins. Connexin40 (Cx40) and Cx43 are the dominant connexins in atrial myocytes, while Cx45 is mostly expressed in the sinoatrial (SA) and atrioventricular (AV) nodes which directly connect nodal cells with atrial myocytes, possibly via heterotypic Cx40/Cx45 and/or Cx43/Cx45 GJs.

Engineered Cx40 variants increased docking and function of heterotypic Cx40/Cx43 gap junction channels.

Gap junction (GJ) channels provide low resistance passages for rapid action potential propagation in the heart. Both connexin40 (Cx40) and Cx43 are abundantly expressed in and frequently co-localized between atrial myocytes, possibly forming heterotypic GJ channels. However, conflicting results have been obtained on the functional status of heterotypic Cx40/Cx43 GJs.

Atrial fibrillation-linked germline GJA5/connexin40 mutants showed an increased hemichannel function.

Mutations in GJA5 encoding the gap junction protein connexin40 (Cx40) have been linked to lone atrial fibrillation. Some of these mutants result in impaired gap junction function due to either abnormal connexin localization or impaired gap junction channels, which may play a role in promoting atrial fibrillation. However, the effects of the atrial fibrillation-linked Cx40 mutants on hemichannel function have not been studied.