Correspondence
The Long-QT Syndrome
N Engl J Med 1995; 333:1783-1784December 28, 1995
- Article
To the Editor:
Mutations at various gene loci have recently been shown to cause the long-QT syndrome,1,2 as Towbin (Aug. 10 issue)3 reports. We have studied one of these loci, the human ether-a-go-go–related gene (HERG, the gene for the long-QT syndrome 2, or LQT2, on chromosome 7), by direct sequencing of the major functional regions between the expressed S1 domain and the cyclic-nucleotide–binding domain in 15 patients with the long-QT syndrome. This sequencing resulted in the identification of two new mutations in a highly conserved region of HERG. One patient had a single base-pair deletion (delT1671, with the nucleotide numeration beginning with the methionine start codon), resulting in a premature stop codon within the S5 domain. The likelihood of a causal relation between the defective HERG allele and the clinical disease in this patient's family was established by the subsequent identification of the mutation in two additional affected family members and its absence in two unaffected members. In another patient with the long-QT syndrome, a nonsense mutation in codon 611 (Tyr611End) was found. The patient's family was not available for study. Both mutations result in truncated proteins and a loss of important functional domains of HERG, including the pore domain and the nucleotide-binding domain.4
The identification of additional mutations that alter the HERG gene product in patients with the long-QT syndrome provides further evidence of the important role of this gene in the development of disease. Moreover, the detection of two mutations on sequencing only a minor portion of HERG in 15 persons demonstrates that mutations in this gene are probably a frequent cause of the long-QT syndrome.
4 ReferencesEric Schulze-Bahr, M.D.
Wilhelm Haverkamp, M.D.
Harald Funke, M.D.
University of Münster, D-48129 Münster, Germany1
Curran ME ,Splawski I ,Timothy KW ,Vincent GM ,Green ED ,Keating MT . A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803
CrossRef | Web of Science | Medline2
Wang Q ,Shen J ,Splawski I , et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811
CrossRef | Web of Science | Medline3
Towbin JA . New revelations about the long-QT syndrome. N Engl J Med 1995;333:384-385
Full Text | Web of Science | Medline4
Warmke JW ,Ganetzky B . A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 1994;91:3438-3442
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Towbin replies:
To the Editor: Schulze-Bahr and colleagues report two new mutations within HERG in patients with the long-QT syndrome and speculate that mutations in this gene are a common cause of the syndrome. Assuming that the abnormalities described by Schulze-Bahr et al. are indeed disease-causing mutations (the data are not shown, and no information is presented from an analysis of normal, unrelated controls), this brings the total number of mutations reported in HERG to eight in LQT2.1,2 On the basis of findings in other disorders, it would not be surprising if many different mutations in the gene resulted in one clinical disorder. For instance, more than 30 different mutations have been described in the β-myosin heavy-chain gene in patients with familial hypertrophic cardiomyopathy, and an even larger number of mutations in the dystrophin gene result in Duchenne's and Becker's muscular dystrophies. In both hypertrophic cardiomyopathy and the two types of muscular dystrophy, the specific gene mutation can often predict the clinical severity and outcome of the disease3,4 because of the resultant derangement in the encoded protein produced. Therefore, as more mutations are found in HERG, as well as in the chromosome 3–linked LQT3 gene, SCN5A, 5 it is possible that a variety of these mutations may predict the prognosis and the likelihood of sudden death. Furthermore, since the responsible ion channels identified thus far are different (i.e., LQT2 HERG is a potassium channel, and LQT3 SCN5A is a sodium channel), subtle electrocardiographic differences may distinguish one gene defect from another and specific pharmacologic agents may be useful in treating specific forms.
As Schulze-Bahr et al. demonstrate, a diligent search for the entire disease-causing gene by mutation analysis should result in the identification of new mutations. Other genes in the long-QT syndrome remain elusive. In all likelihood, the chromosome 11–linked LQT1 gene will soon be elucidated, and mutations identified, and the remaining genes will also be discovered in the near future. This information will allow better presymptomatic diagnosis of the long-QT syndrome and an improved understanding of this serious disorder. Identification of these genes and the responsible mutations should help determine the relative benefits of various therapeutic approaches in individual patients.
5 ReferencesJeffrey A. Towbin, M.D.
Baylor College of Medicine, Houston, TX 770301
Curran ME ,Splawski I ,Timothy KW ,Vincent GM ,Green ED ,Keating MT . A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803
CrossRef | Web of Science | Medline2
Towbin JA . New revelations about the long-QT syndrome. N Engl J Med 1995;333:384-385
Full Text | Web of Science | Medline3
Watkins H ,Rosenzweig A ,Hwang D-S , et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108-1114
Full Text | Web of Science | Medline4
Monaco AP ,Bertelson CJ ,Liechti-Gallati S ,Moser H ,Kunkel LM . An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 1988;2:90-95
CrossRef | Medline5
Wang Q ,Shen J ,Splawski I , et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811
CrossRef | Web of Science | Medline
- Citing Articles (11)
Citing Articles
1
Sarah Vergult, Andrew Dauber, Barbara Delle Chiaie, Elke Van Oudenhove, Marleen Simon, Ali Rihani, Bart Loeys, Joel Hirschhorn, Jean Pfotenhauer, John A Phillips, Shehla Mohammed, Caroline Ogilvie, John Crolla, Geert Mortier, Björn Menten. (2011) 17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations. European Journal of Human Genetics
CrossRef2
Hai-Tao Yang, Chao-Feng Sun, Chang-Cong Cui, Xiao-Lin Xue, Ai-Feng Zhang, Hong-Bing Li, Dong-Qi Wang, Juan Shu. (2009) HERG-F463L POTASSIUM CHANNELS LINKED TO LONG QT SYNDROME REDUCE I Kr CURRENT BY A TRAFFICKING-DEFICIENT MECHANISM. Clinical and Experimental Pharmacology and Physiology 36:8, 822-827
CrossRef3
Chern-En Chiang, Dan M Roden. (2000) The long QT syndromes: genetic basis and clinical implications. Journal of the American College of Cardiology 36:1, 1-12
CrossRef4
JEFFREY A. TOWBIN, MATTEO VATTA. (2000) The Genetics of Cardiac Arrhythmias. Pacing and Clinical Electrophysiology 23:1, 106-119
CrossRef5
Matteo Vatta, Hua Li, Jeffrey A. Towbin. (2000) Molecular biology of arrhythmic syndromes. Current Opinion in Cardiology 15:1, 12-22
CrossRef6
Jeffrey A Towbin, Matteo Vatta, Zhiquing Wang, Neil E Bowles, Hua Li. (1999) Emerging targets in the long QT syndromes and Brugada syndrome. Expert Opinion on Therapeutic Targets 3:3, 423-437
CrossRef7
Igor Splawski, Jiaxiang Shen, Katherine W. Timothy, G.Michael Vincent, Michael H. Lehmann, Mark T. Keating. (1998) Genomic Structure of Three Long QT Syndrome Genes:KVLQT1, HERG,andKCNE1. Genomics 51:1, 86-97
CrossRef8
Kaoru Akimoto, Michiko Furutani, Shin-Ichiro Imamura, Yoshiyuki Furutani, Hiroshi Kasanuki, Atsuyoshi Takao, Kazuo Momma, Rumiko Matsuoka. (1998) Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family. Human Mutation 11:S1, S184-S186
CrossRef9
Qing Wang, Qiuyun Chen, Jeffrey A Towbin. (1998) Genetics, molecular mechanisms and management of long QT syndrome. Annals of Medicine 30:1, 58-65
CrossRef10
Eric Schulze-Bahr, Qing Wang, Horst Wedekind, Wilhelm Haverkamp, Qiuyun Chen, Yaling Sun, Claudia Ruble, Marco Hördt, Jeffrey A. Towbin, Martin Borggrefe, Gerd Assmann, Xiangdong Qu, John C. Somberg, Günter Breithardt, Carlos Oberti, Harald Funke. (1997) KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nature Genetics 17:3, 267-268
CrossRef11
A. Lafeuillade, P. Pellegrino, Cécile Poggi, Nérina Profizi. (1996) Quantitative molecular monitoring of HIV-1 RNA during antiretroviral therapy. Infection 24:6, 412-418
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