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SCN5A mutation in Chinese patients with arrhythmogenic right ventricular dysplasia

SCN5A-Mutation bei chinesischen Patienten mit arrhythmogener rechtsventrikulärer Dysplasie

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Abstract

Background

Arrhythmogenic right ventricular dysplasia (ARVD) is a genetically determined disorder, characterized by two components: cardiomyopathy and arrhythmia. To date, the ion channel-related pathogenesis underlying this phenomenon has been poorly understood. The aim of this study was to systematically evaluate the sodium channel variants in Chinese patients with ARVD.

Patients and methods

Patients meeting the diagnostic guidelines of ARVD revised in 2010 were enrolled. All exons and exon-intron boundaries of the SCN5A gene and desmosomal genes known to be associated with ARVD, including DSC2, DSG2, DSP, JUP, and PKP2, were sequenced by direct DNA sequencing. A total of 12 unrelated index patients were included in the study.

Results

Eight of the patients developed ventricular tachycardia (VT) and ventricular fibrillation (VF), one of them showed epsilon wave, one of them showed type-1 Brugada wave, seven of them exhibited syncope or dizziness, and none of the patients had a family history of SCD. A new missense heterozygote mutation, I137M, in SCN5A was found in proband 5 with recurrent palpitations and a high incidence of VT. I137M is in exon 4 of SCN5A, at the S1 segment in domain I of Nav1.5, which predicted a substitution of isoleucine for methionine at codon site 137 (p. Ile137Met, I137M). I137M was not detected in 400 healthy control chromosomes from individuals of the same ethnic background, which indicated that this mutation was a conservative site in the SCN5A gene, and the encoded protein Nav1.5 might have a functional defect resulting in arrhythmia.

Conclusion

This was the first study to systematically investigate sodium channel variants in Chinese patients with ARVD; a new SCN5A mutation, I137M, was found. This finding may provide new evidence of the genetic pathogenesis of ARVD in Chinese patients, implying that the SCN5A gene should be screened in patients with ARVD and VT/VF.

Zusammenfassung

Hintergrund

Die arrhythmogene rechtsventrikuläre Dysplasie (ARVD) ist eine genetisch geprägte Erkrankung, die durch 2 Komponenten gekennzeichnet ist, Kardiomyopathie und Arrhythmie. Bisher ist die eisenkanalabhängige Pathogenese dieses Phänomens nur unzureichend bekannt. Ziel der vorliegenden Studie war es, die Kaliumkanalvarianten bei chinesischen Patienten mit ARVD systematisch zu untersuchen.

Patienten und Methoden

In die Studie aufgenommen wurden Patienten, welche die diagnostischen Kriterien einer ARVD nach den 2010 revidierten Leitlinien erfüllten. Bei sämtlichen Exons und Exon-Intron-Grenzen des SCN5A-Gens und desmosomaler Gene mit bekanntem Zusammenhang mit ARVD, einschließlich DSC2, DSG2, DSP, JUP und PKP2, erfolgte eine direkte DNA-Sequenzierung. Insgesamt wurden 12 nicht miteinander verwandte Indexpatienten aufgenommen.

Ergebnisse

Von ihnen entwickelten 8 eine ventrikuläre Tachykardie (VT) und Kammerflimmern (VF), einer wies eine Epsilonwelle auf, einer eine Welle vom Typ 1 nach Brugada, 7 litten unter Synkopen oder Schwindel, aber bei keinem war ein plötzlicher Herztod in der Familienanamnese zu eruieren. Eine neue heterozygote Missense-Mutation, I137M, wurde in SCN5A bei Proband 5 mit rezidivierenden Palpitationen und einer hohen VT-Inzidenz festgestellt. I137M liegt in Exon 4 von SCN5A, auf dem S1-Segment in Domäne I von Nav1.5 und bezeichnet den Austausch von Isoleucin durch Methionin an der Codonstelle 137 (p. Ile137Met, I137M). I137M wurde bei 400 gesunden Kontrollchromosomen von Personen mit demselben ethnischen Hintergrund nicht gefunden, was darauf hinweist, dass diese Mutation eine konservierte Stelle im SCN5A-Gen betrifft und das codierte Protein Nav1.5 möglicherweise einen funktionellen Defekt aufweist, der zu einer Arrhythmie führt.

Schlussfolgerung

Erstmals wurden die Kaliumkanalvarianten bei chinesischen Patienten mit ARVD systematisch untersucht und eine neue SCN5A-Mutation, I137M, gefunden. Dieses Ergebnis stellt möglicherweise einen neuen Hinweis auf die genetische Pathogenese der ARVD bei chinesischen Patienten dar, was impliziert, dass das SCN5A-Gen bei Patienten mit ARVD und VT/VF untersucht werden sollte.

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China [30760076,81070148,8116002] and the China Ministry of Education [IRT1141, 2011360111000 2]. Authors’ contributions: J.Y. collected the patient samples and made the diagnosis; J.H. carried out the molecular genetic studies and participated in the sequence alignment; X.D., Q.C. (Qing Cao), and X.L. (Xin Liu) carried out the molecular genetic studies; Q.X. and X.L. (Xiuxia Liu) carried out the DNA extraction; Y.S. and Q.C. (Qi Chen) help to draft the manuscript and discussed the results; W.H. performed the clinical diagnosis and coordination; K.H. designed the experimental protocol, analyzed the sequences, and drafted the manuscript.

Compliance with ethical guidelines

Conflict of interest. J. Yu, J. Hu, X. Dai, Q. Cao, Q. Xiong, X. Liu, X. Liu, Y. Shen, Q. Chen, W. Hua, and K. Hong state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Authors and Affiliations

  1. The Cardiology Department, The Second Affiliated Hospital of NanChang University, 330006, Jiangxi, China

    J. Yu, J. Hu, X. Dai, Q. Xiong, X. Liu, Y. Shen, Q. Chen &  K. Hong

  2. The Jiangxi Key Laboratory of Molecular Medicine, 330006, Jiangxi, China

    Q. Cao, X. Liu &  K. Hong

  3. Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    W. Hua

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  1. J. Yu
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Correspondence to K. Hong.

Additional information

J. Yu and J. Hu contributed equally to this paper.

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Yu, J., Hu, J., Dai, X. et al. SCN5A mutation in Chinese patients with arrhythmogenic right ventricular dysplasia. Herz 39, 271–275 (2014). https://doi.org/10.1007/s00059-013-3998-5

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  • DOI: https://doi.org/10.1007/s00059-013-3998-5

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