A heterozygous missense SCN5A mutation associated with early repolarization syndrome.

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.