PMC:3480677 / 8911-13035 JSONTXT

{"project":"2_test","denotations":[{"id":"23105938-10471492-44845448","span":{"begin":586,"end":587},"obj":"10471492"},{"id":"23105938-1309946-44845449","span":{"begin":1114,"end":1115},"obj":"1309946"},{"id":"23105938-1309946-44845450","span":{"begin":1330,"end":1331},"obj":"1309946"},{"id":"23105938-1309946-44845451","span":{"begin":1469,"end":1470},"obj":"1309946"},{"id":"23105938-15161528-44845452","span":{"begin":1472,"end":1474},"obj":"15161528"},{"id":"23105938-15338453-44845453","span":{"begin":1476,"end":1478},"obj":"15338453"},{"id":"23105938-12639704-44845454","span":{"begin":1695,"end":1697},"obj":"12639704"},{"id":"23105938-12454206-44845455","span":{"begin":1846,"end":1848},"obj":"12454206"},{"id":"23105938-12569159-44845456","span":{"begin":1850,"end":1852},"obj":"12569159"},{"id":"23105938-18245395-44845457","span":{"begin":2743,"end":2745},"obj":"18245395"},{"id":"23105938-15689442-44845458","span":{"begin":2747,"end":2749},"obj":"15689442"},{"id":"23105938-11804990-44845459","span":{"begin":3451,"end":3453},"obj":"11804990"},{"id":"23105938-11234013-44845460","span":{"begin":3463,"end":3465},"obj":"11234013"},{"id":"23105938-20025708-44845461","span":{"begin":3476,"end":3478},"obj":"20025708"},{"id":"23105938-11748104-44845462","span":{"begin":3489,"end":3491},"obj":"11748104"},{"id":"23105938-11804990-44845463","span":{"begin":3506,"end":3508},"obj":"11804990"}],"text":"Discussion\nThis is the first case report with genetic variations of SCN5A in Korean patients with AVB. To date, a number of SCN5A variations associated with various cardiac diseases, such as LQT, Brs, progressive cardiac conduction defect, AF, and overlapping syndromes, have been reported. Although SCN5A genetic variations associated with AVB have been well studied in Caucasians, Han Chinese, and Japanese, no study has yet been published in Koreans as far we know. In previous studies, it has been shown that in some cases, progressive AVB has been linked to SCN5A gene variations [4]. Furthermore, in our prior study, 2 novel variations were detected in Korean sick sinus syndrome (SSS) patients, which, to our knowledge, has not been previously reported in any ethnic group.\nThe variations could be significantly associated with functional effects of the SCN5A gene. Based on these results, we searched for SCN5A genetic variations in Korean AVB and compared them with those of control subjects. The SCN5A gene consists of 28 exons and encodes a protein of 2016 amino acids with a molecular mass of 227 kDa [7]. In our patients with AVB, there were 7 sites of nucleotide change from exon 2 to exon 28 of the SCN5A gene. Among of them, 2 sites (G87A-A29A, IVS9-3C \u003e A) were reported as genetic variations in a Western study [7], and T5457C-D1819D has already been reported as a variation or polymorphism without functional effects on the channel in Asian studies [7, 15, 16]. A1673G-H558R is located in the Na+ channel I, II interdomain linker, and previous functional studies have shown that the H558R-encoding minor allele can alter the phenotype of true disease-causing SCN5A mutations [17]. It has been suggested that it modulates Na+ channel functional changes caused by other variations and plays a role in intragenic complementation [18, 19]. Previously, the H558R G allele has been associated with occurrence of early-onset AF and LQT interval in healthy populations. The H558R G allele frequency has been reported to be 20.4-32% in the white population, 29% in the black population, and 10.4% in the Chinese population. In our study, the G allele frequency of SCN5A mutation carriers was 8% and 13.1% in the normal control group.\nG3578A-R1193Q, which can cause a gain of the sodium ion channel function and cause LQT3 and Brs, was also found. It has been reported that G3578A-R1193Q confers a risk of LQT3 or Brs in the general population, although it seems to be a common polymorphism in the Han Chinese population. Electrophysiological studies showed that R1193Q destabilizes inactivation gating and generates a persistent, non-inactivating current, which results in a gain of the sodium channel function, as in LQT3 syndrome [20, 21].\nIn addition to previously reported variations, we identified 2 novel variations that were not reported in the case of Japanese and Chinese populations. One of these variations was heterozygous non-synonymous (C48G-F16L), and the other was heterozygous synonymous (G3048A-T1016T). Since a non-synonymous nucleotide change in the SCN5A gene is likely to induce a functional change in the sodium channel, a non-synonymous substitution was considered a candidate for the variation associated with this disorder. In this study, a non-synonymous variation, C48G-F16L, was not found in the normal control group but was detected only in the patient group, suggesting that it may effect AVB. However, G298S [11], G514C [12], P1008S [13], G1406R [14], and D1595N [11], identified in other ethnic populations, were not detected, thought to be due to very low frequency or no variation in the Korean population.\nIn summary, our data may provide useful information for the identification of novel variations related to AVB, and the novel variants may provide useful bio-markers to study Korean cardiac disease.\nIn a future study, we will conduct a functional analysis of the novel variation (C48G-F16L) and propose a mechanism for its contribution to the AVB phenotype in patients. Also, we will try to find out genetic variation sites in other genes that might be responsible for AVB."}