Idetification of CACNA1B (p.K567R) mutation responsible for familiar AVNRT

Abstract

AbstractAtrioventricular nodal reentry tachycardia (AVNRT) is the most common form of paroxysmal supraventricular tachycardia (PSVT). The exact cause of AVNRT has not yet been found. However, an increasing number of reports suggest that AVNRT is hereditary, but no precise pathogenic gene has been found so far. In our study, we found that a point mutation of CACNA1B (p.K567R) which encoded the α1 subunit of N-type calcium channel (Cav 2.2), was cosegregated with AVNRT in one family. Previous research showed that overexpression and point mutations of human CACNA1B in zebrafish embryos may be related to abnormal heart rate. Telemetric ECG recordings showed that rats with a CACNA1B point mutation displayed sporadic supraventricular tachycardia and altered QRS complex morphology. In addition, the CACNA1B (p.K567R) rats presented a double path phenomenon and AVNRT induction by intracardiac electrophysiological examination. Indexes of heart rate variance in CACNA1B mutation rats showed an in cardiac sympathetic activity and an imbalance of cardiac sympathetic and parasympathetic activity. Single-cell RNA sequencing indicated that the number of neurons in the superior cervical ganglion (SCG) of mutant rats was higher than in wild-type (WT) rats, accompanied by an increased expression of CACNA1B. Functional enrichment in SCG proteomics suggests that point mutant rats have abnormalities in synaptic function and ion transport, which could lead to the release of neurotransmitters. This could affect the cardiac autonomic neural activity and lead to an imbalance in sympathetic and parasympathetic activity and the subsequent occurrence of AVNRT. Our findings indicate that CACNA1B (p.K567R) is the pathogenic gene of AVNRT in familial AVNRT and confirm that CACNA1B is the first definitive AVNRT pathogenic gene that has been discovered.