Author + information
- Yubi Lin1
We identified familial arrhythmia of Brugada syndrome, atrial fibrillation, sick sinus syndrome and progressive conduction block, collectively designated “cardiac sodium channel overlap syndrome (CSCOS)”, in a Chinese Han family and investigated the underlying genetic mechanisms.
Genetic analysis was conducted for probands in the coding and splicing regions of genes susceptible for cardiac arrhythmia diseases. A functional study of novel mutants was performed in human embryonic kidney 293 cells (HEK293) using the voltage clamp technique
We identified a rare double mutant of SCN5A, R965C and R1309H. R965 and R1309 residues are highly conserved across all species. Furthermore, R965C is associated with Brugada syndrome. Compared to wild-type (WT) cells, Na+ current density was markedly reduced by 76% in cells carrying the R1309H mutant at membrane potentials ranging from −50 mV to −10 mV. The slope of R1309H-carrying cells was significantly less steep than that of WT cells (P<0.001). Steady-state inactivation of R1309H cells was significantly left-shifted from that of WT cells at test potentials of −100 mV to −80 mV. The voltage of half-maximal inactivation for R1309H cells was significantly left-shifted by ∼11.22 mV from that of WT cells (P<0.01).
While the SCN5A R965C mutant appears solely related to Brugada syndrome, the R1309H mutant causes significant loss of function of the Nav1.5 sodium channel, which is potentially a key mechanism underlying familial CSCOS.