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      Molecular pathogenesis of long QT syndrome type 1

      review-article
      Author(s): , PhD a , b , c , * , , MD, PhD c , , MD, PhD b
      Publication date (Electronic):
      Journal: Journal of Arrhythmia
      Publisher: Elsevier
      Keywords: LQT1, KCNQ1, Genotype-phenotype correlations, Adrenergic regulation

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          Abstract

          Long QT syndrome type 1 (LQT1) is a subtype of a congenital cardiac syndrome caused by mutation in the KCNQ1 gene, which encodes the α-subunit of the slow component of delayed rectifier K + current ( I Ks) channel. Arrhythmias in LQT1 are characterized by prolongation of the QT interval on ECG, as well as the occurrence of life-threatening cardiac events, frequently triggered by adrenergic stimuli (e.g., physical or emotional stress). During the past two decades, much advancement has been made in understanding the molecular pathogenesis underlying LQT1. Uncovering the genotype-phenotype correlations in LQT1 is of clinical importance to better understand the gene-specific differences that may influence the propensity for developing life-threatening arrhythmias under specific conditions. Elucidation of these mechanisms will also help to improve the diagnosis and management of this cardiac disorder based on gene-specific considerations. This review describes the current medical consensus and recent developments regarding the molecular pathogenesis of LQT1 and provides a novel insight into the adrenergic regulation of this disease.

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          SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

          Q. Wang, J. Shen, I Splawski … (1995)
          Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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            Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

            Peter J. Schwartz, Silvia G Priori, Carla Spazzolini … (2001)
            The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
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              Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.

              J. E. M. Robinson, Margaret M. Lehmann, Alexander Towbin … (2000)
              Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals). KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.
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                Author and article information

                Contributors
                Jie Wu
                Wei-Guang Ding
                Minoru Horie
                Journal
                Journal ID (nlm-ta): J Arrhythm
                Journal ID (iso-abbrev): J Arrhythm
                Title: Journal of Arrhythmia
                Publisher: Elsevier
                ISSN (Print): 1880-4276
                ISSN (Electronic): 1883-2148
                Publication date PMC-release: 27 January 2016
                Publication date (Print): October 2016
                Publication date (Electronic): 27 January 2016
                Volume: 32
                Issue: 5
                Pages: 381-388
                Affiliations
                [a ]Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 710061, Xi׳an, China
                [b ]Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan
                [c ]Department of Physiology, Shiga University of Medical Science, Otsu 520-2192, Japan
                Author notes
                [* ]Corresponding author at: Department of Pharmacology, School of Basic Medical Sciences, Xi׳an Jiaotong University Health Science Center, 710061 Xi׳an, China. Tel.: +86 158 2930 7580.Department of Pharmacology, School of Basic Medical Sciences, Xi׳an Jiaotong University Health Science CenterXi׳an710061China wujie@ 123456mail.xjtu.edu.cn
                Article
                Publisher ID: S1880-4276(16)00004-1
                DOI: 10.1016/j.joa.2015.12.006
                PMC ID: 5063268
                SO-VID: 4bbcf9b9-dcfd-4d58-936d-b68e88071337
                Copyright © © 2016 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 12 August 2015
                Date revision received : 16 November 2015
                Date accepted : 17 December 2015
                Categories
                Subject: Review

                Keywords: lqt1,kcnq1,genotype-phenotype correlations,adrenergic regulation
                Data availability:
                Keywords: lqt1, kcnq1, genotype-phenotype correlations, adrenergic regulation

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