Abstract
The SCN5A gene encodes for the INa channel implicated in long QT syndrome type-3 (LQTS-type-3). Clinical symptoms of this type are lethal as most patients had a sudden death during sleep. Screening of SCN5A in South Indian cohort by PCR-SSCP analyses revealed five polymorphisms — A29A (exon-2), H558R (exon-12), E1061E and S1074R (exon-17) and IVS25+65G>A (exon-25) respectively. In-silico and statistical analyses were performed on all the polymorphisms.Exon-2 of SCN5A gene revealed A282G polymorphism (rs6599230), resulting in alanine for alanine (A29A) silent substitution in the N-terminus of SCN5A protein. Exon-12 showed A1868G polymorphism (H558R — rs1805124) and its ‘AA’ genotype and ‘A’ allele frequency were found to be higher in LQTS patients pointing towards its role in LQTS etiology.Two polymorphisms A3378G (E1061E) and the novel C3417A (S1074R) were identified as compound heterozygotes/genetic compounds in exon-17 of SCN5A located in the DIIS6–DIIIS1 domain of the SCN5A transmembrane protein. IVS25+65G>A was identified in intron-25 of SCN5A. The ‘G’ allele was identified as the risk allele.Variations were identified in in-silico analyses which revealed that these genetic compounds may lead to downstream signaling variations causing aberrations in sodium channel functions leading to prolonged QTc. The compound heterozygotes of SCN5A gene polymorphisms revealed a significant association which may be deleterious/lethal leading to an aberrant sodium ion channel causing prolonged QTc.
Highlights
NaV channels of the heart are important for the orderly progression of action potentials from the sinoatrial node, through the atria, across the atrioventricular node, along the specialized conduction system of the ventricles (His–Purkinje system), and throughout the myocardium to stimulate rhythmic contraction (George, 2005)
Late INa has been demonstrated in cardiac ventricular specimens of various mammalian species including humans, and its role has been documented in the generation of normal as well as altered action potential (AP) durations (Maltsev et al, 1998; Berecki et al, 2006)
Blood samples were collected for molecular analyses from confirmed 46 Long QT syndrome (LQTS) probands and 69 first degree relatives from Care Hospitals, Hyderabad, Sri Jayadeva Institute of Cardiovascular Science and Research, Bangalore, Institute of Maternal and Child Health, Calicut Medical College, Calicut and Krishna Institute of Medical Sciences, Hyderabad
Summary
NaV channels of the heart are important for the orderly progression of action potentials from the sinoatrial node, through the atria, across the atrioventricular node, along the specialized conduction system of the ventricles (His–Purkinje system), and throughout the myocardium to stimulate rhythmic contraction (George, 2005). Channels open and inactivate rapidly during depolarization, and reopen during the plateau and repolarization phases, carrying ‘persistent’ or ‘late’ inward current (late INa). Late INa has been demonstrated in cardiac ventricular specimens of various mammalian species including humans, and its role has been documented in the generation of normal as well as altered action potential (AP) durations (Maltsev et al, 1998; Berecki et al, 2006). Genotype Controls n (%) LQTS n (%) FDR n (%). Allele Controls LQTS FDRs GG 29 (19).
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