期刊
MOLECULAR MEDICINE REPORTS
卷 13, 期 6, 页码 5216-5222出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2016.5162
关键词
Brugada syndrome; sodium voltage-gated channel subunit 5; sudden cardiac death; genetics; patch-clamp technique; channelopathies
资金
- National Natural Science Foundation of China [81270277, 81170090]
Brugada syndrome (BrS) is an inherited primary arrhythmia disorder, leading to sudden cardiac death due to ventricular tachyarrhythmia, but does not exhibit clinical cardiac abnormalities. The sodium voltage-gated channel subunit 5 (SCN5A) gene, which encodes the subunit of the cardiac sodium channel, Nav1.5, is the most common pathogenic gene, although 22 BrS-susceptibility genes have previously been identified. In the present study, a novel genetic variant (p.D1690N) localized in the S5-S6 linker of domain IV of the Nav1.5 channels was identified in a Chinese Han family. Wild-type (WT) and p.D1690N Nav1.5 channels were transiently over-expressed in HEK293 cells and analyzed via the whole-cell patch clamp technique. The p.D1690N mutation significantly reduced the peak sodium current density to 23% of WT (at -20 mV; P<0.01), shifted steady-state activation by 7 mV to increasingly positive potentials (P<0.01). Furthermore, prolonging of the recovery from inactivation was observed in the p.D1690N mutant. No significant change was identified in steady-state inactivation. Thus, the mutant-induced changes contributed to the loss of function of Nav1.5 channels, which indicates that the p.D1690N variant may have a pathogenic role in BrS.
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