State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.
Int J Mol Med. 2013 Sep;32(3):661-7. doi: 10.3892/ijmm.2013.1422. Epub 2013 Jun 21.
The genetic background of early repolarization syndrome (ERS) has not been fully understood. In this study, we identified a missense SCN5A mutation and a polymorphism in a patient with ERS and characterized the functional consequences of the two variants. The functional consequences of mutant channels were investigated with the patch-clamp technique, immunocytochemical studies and real-time PCR. A 19-year-old female proband with recurrent syncope had a documented electrocardiogram with ventricular fibrillation (VF) proceeded by large J waves in leads I, II, III, aVF and V2-V6. Genetic analysis revealed that the patient carried a missense mutation of c.4297 G>C and a synonymous polymorphism of T5457C on the same allele of the SCN5A gene. Patch-clamp experiments demonstrated that the c.4297 G>C mutation significantly reduced the sodium current (INa) density and altered the channel kinetics. Immunocytochemical studies demonstrated that the mutation dramatically inhibited the expression of sodium channels in the cell membrane and in the cytoplasm, although the mRNA levels remained in the normal range. Noteworthy, the reduction in INa density may be partially restored from the co-existence of the T5457C polymorphism on the same allele by the upregulation of mRNA levels. In conclusion, our study indicated that the c.4297 G>C mutation caused the 'loss-of-function' of sodium channels that may account for the clinical phenotype of ERS. The reduction in INa density was due to a decreased number of sodium channels caused by abnormal translation processes. The T5457C polymorphism partially rescued the INa density of the mutant channels by the upregulation of mRNA levels.
早期复极综合征（ERS）的遗传背景尚未完全阐明。在这项研究中，我们在一位 ERS 患者中鉴定出一个错义 SCN5A 突变和一个多态性，并对这两种变体的功能后果进行了表征。使用膜片钳技术、免疫细胞化学研究和实时 PCR 研究了突变通道的功能后果。一位 19 岁的女性先证者反复晕厥，其心电图记录到心室颤动（VF）前导联 I、II、III、aVF 和 V2-V6 中有大 J 波。基因分析显示，该患者携带 SCN5A 基因同一等位基因上的 c.4297 G>C 错义突变和 T5457C 同义多态性。膜片钳实验表明，c.4297 G>C 突变显著降低了钠电流（INa）密度并改变了通道动力学。免疫细胞化学研究表明，尽管 mRNA 水平仍处于正常范围，但突变显著抑制了细胞膜和细胞质中钠通道的表达。值得注意的是，通过同一等位基因上 T5457C 多态性的共存，mRNA 水平的上调可能部分恢复 INa 密度的降低。总之，我们的研究表明，c.4297 G>C 突变导致钠通道的“失活”，这可能是 ERS 临床表型的原因。INa 密度的降低是由于异常翻译过程导致钠通道数量减少所致。T5457C 多态性通过上调 mRNA 水平部分挽救了突变通道的 INa 密度。
