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Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome.

ABSTRACT: BACKGROUND AND OBJECTIVES:Due to recent studies that have shown an association between the genetic variation of SCN5A and sick sinus syndrome (SSS), we sought to determine if a similar correlation existed in Korean patients with SSS. SUBJECTS AND METHODS:We enrolled 30 patients with SSS who showed a sinus pause (longer than 3.0 s) in Holter monitoring, in addition to 80 controls. All exons including the putative splicing sites of the SCN5A gene were amplified by polymerase chain reaction and sequenced either directly or following subcloning. Wild-type and single nucleotide polymorphisms were expressed in human embryonic kidney cells, and the peak sodium current (INa ) was analyzed using the whole-cell patch-clamp technique. RESULTS:A total of 9 genetic variations were identified: 7 variations (G87A-A29A, IVS9-3C>A, A1673G-H558R, G3823A-D1275N, T5457C-D1819D, T5963G-L1988R, and C5129T-S1710L) had been previously reported, and 2 variants (A3075T-E1025D and T4847A-F1616Y) were novel; the potential structural effects of F1616Y were analyzed in a three-dimensional model of the SCN5A domain. Patch-clamp studies at room temperature demonstrated that the peak INa was significantly increased by 140% in HEK cells transfected with F1616Y compared with wild-type (-335.13 pA/pF±24.04, n=8 vs. -139.95 pA/pF±23.76, n=7, respectively). Furthermore, the voltage dependency of the activation and steady-state inactivation of F1616Y were leftward-shifted compared with wild-type (Vh activation=-55.36 mv±0.22, n=8 vs. Vh activation=-44.21 mV±0.17, n=7; respectively; Vh inactivation=-104.47 mV±0.21, n=7 vs. Vh inactivation=-84.89 mV±0.09, n=12, respectively). CONCLUSION:F1616Y may be associated with SSS.

SUBMITTER: Lee YS

PROVIDER: S-EPMC4720851 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome.

Lee Young Soo YS Olaopa Michael A MA Jung Byung Chun BC Lee Sang Hee SH Shin Dong Gu DG Park Hyoung Seob HS Cho Yongkeun Y Han Sang Mi SM Lee Myung Hoon MH Kim Yoon Nyun YN

Korean circulation journal 20160114 1

<h4>Background and objectives</h4>Due to recent studies that have shown an association between the genetic variation of SCN5A and sick sinus syndrome (SSS), we sought to determine if a similar correlation existed in Korean patients with SSS.<h4>Subjects and methods</h4>We enrolled 30 patients with SSS who showed a sinus pause (longer than 3.0 s) in Holter monitoring, in addition to 80 controls. All exons including the putative splicing sites of the SCN5A gene were amplified by polymerase chain r ...[more]

PMID: 26798387

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Project description:Sick sinus syndrome (SSS) is a sinus node dysfunction characterized by severe sinus bradycardia. SSS results in insufficient blood supply to the brain, heart, kidneys, and other organs and is associated with the increased risk of sudden cardiac death. Bradyarrhythmia appears in the absence of any associated cardiac pathology and displays a genetic legacy. The present study identified a family with primary manifestation of sinus bradycardia (five individuals) along with early repolarization (four individuals) and atrial fibrillation (one individual). Targeted exome sequencing was used to screen exons and adjacent splice sites of 61 inherited arrhythmia?associated genes, to detect pathogenic genes and variant sites in the proband. Family members were sequenced by Sanger sequencing and protein functions predicted by Polyphen?2 software. A total of three rare variants were identified in the family, including two missense variants in calcium voltage?gated channel subunit alpha1 C (CACNA1C) (gi:193788541, NM_001129843), c.1786G>A (p.V596M) and c.5344G>A (p.A1782T), and one missense variant in titin (TTN) c.49415G>A (p.R16472H) (gi:291045222, NM_003319). The variants p.V596M and p.R16472H were predicted to be deleterious and resulted in alterations in the amino acid type and sequence of the polypeptide chain, which may partially or completely inactivate the encoded protein. The comparison of literature, gene database, and pedigree phenotype analysis suggests that p.V596M or p.R16472H variants are pathogenic. The complex overlapping variants at three loci lead to a more severe phenotype in the proband, and may increase the susceptibility of individuals to atrial fibrillation. The simultaneous occurrence of V596M and R16472H may increase the severity of early repolarization. Various family members may have carried heterozygous mutants of p.A1782T and p.R16472H due to genetic heterogeneity, however did not exhibit clinical signs of cardiac electrophysiological alterations, potentially attributable to the low vagal tone. To the best of the author's knowledge, this is the first study to suggest the involvement of the novel missense CACNA1C c.1786G>A and TTN c.49415G>A variants in the inheritance of symptomatic bradycardia and development of SSS.

Dataset Information

Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome.

Publications

Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome.

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