title: Mutational analysis of SCN5A gene in long QT syndrome.
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.
authors.affiliation: Dept. of Genetics, University College of Science, Osmania University, Hyderabad 500007, Andhra Pradesh, India.
authors.forename: Sameera Fatima
authors.initials: SF
authors.lastname: Qureshi
authors.affiliation: Dept. of Genetics, University College of Science, Osmania University, Hyderabad 500007, Andhra Pradesh, India.
authors.forename: Altaf
authors.initials: A
authors.lastname: Ali
authors.affiliation: Dept. of Genetics, University College of Science, Osmania University, Hyderabad 500007, Andhra Pradesh, India.
authors.forename: Princy
authors.initials: P
authors.lastname: John
authors.affiliation: Dept. of Genetics, University College of Science, Osmania University, Hyderabad 500007, Andhra Pradesh, India.
authors.forename: Amol P
authors.initials: AP
authors.lastname: Jadhav
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad 500016, Andhra Pradesh, India.
authors.forename: Ananthapur
authors.initials: A
authors.lastname: Venkateshwari
authors.affiliation: Krishna Institute of Medical Sciences, 1-8-31/1, Minister Road, Secunderabad 500 003, Andhra Pradesh, India.
authors.forename: Hygriv
authors.initials: H
authors.lastname: Rao
authors.affiliation: Institute of Maternal and Child Health, Calicut Medical College, Calicut 8, Kerala, India.
authors.forename: M P
authors.initials: MP
authors.lastname: Jayakrishnan
authors.affiliation: Care Hospital, Hyderabad, Andhra Pradesh, India.
authors.forename: Calambur
authors.initials: C
authors.lastname: Narasimhan
authors.affiliation: Sri Jayadeva Institute of Cardiovascular Science and Research, Jayanagar 9th Block, Bannerghatta Road, Bangalore 560069, Karnataka, India.
authors.forename: Jayaprakash
authors.initials: J
authors.lastname: Shenthar
authors.affiliation: Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, Andhra Pradesh, India.
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Thangaraj
authors.affiliation: Dept. of Genetics, University College of Science, Osmania University, Hyderabad 500007, Andhra Pradesh, India.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Nallari
keywords: Compound heterozygotes; FDRs, First degree relatives; LQT3, Long QT syndrome type-3; LQTS; LQTS, Long QT syndrome; Polymorphisms; SCN5A; SCN5A, Sodium channel, voltage-gated, type V, alpha subunit; cLQTS, Congenital long QT syndrome