Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations

Hsueh Chia-Hsiang, Chen Wen-Pin, Lin Jiunn-Lee, Tsai Chia-Ti, Liu Yen-Bin, Juang Jyh-Ming, Tsao Hsuan-Ming, Su Ming-Jai, Lai, Lai Ling-Ping

Description

The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2009
• Nombre de lectures: 3
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Journal of Biomedical Science

BioMedCentral

Open Access Research Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations 1 12 2 ChiaHsiang Hsueh, WenPin Chen, JiunnLee Lin, ChiaTi Tsai, Yen 2 23 1 Bin Liu, JyhMing Juang, HsuanMing Tsao, MingJai Suand Ling 1,2 Ping Lai*

1 2 Address: Instituteof Pharmacology, School of Medicine, National Taiwan University, Taipei, Taiwan,Department of Internal Medicine, National 3 Taiwan University Hospital, Taipei, Taiwan andDepartment of Internal Medicine, ILan Hopital, ILan, Taiwan Email: ChiaHsiang Hsueh  [e-mail]; WenPin Chen  [e-mail]; JiunnLee Lin  [e-mail]; Chia Ti Tsai  [e-mail]; YenBin Liu  [e-mail]; JyhMing Juang  [e-mail]; Hsuan Ming Tsao  [e-mail]; MingJai Su  [e-mail]; LingPing Lai*  [e-mail] * Corresponding author

Published: 20 February 2009Received: 6 November 2008 Accepted: 20 February 2009 Journal of Biomedical Science2009,16:23 doi:10.1186/1423-0127-16-23 This article is available from: http://www.jbiomedsci.com/content/16/1/23 © 2009 Hsueh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract The Brugada syndrome is characterized by ST segment elevation in the right precodial leads V1-V3 on surface ECG accompanied by episodes of ventricular fibrillation causing syncope or even sudden death. The molecular and cellular mechanisms that lead to Brugada syndrome are not yet completely understood. However, SCN5A is the most well known responsible gene that causes Brugada syndrome. Until now, more than a hundred mutations in SCN5A responsible for Brugada syndrome have been described. Functional studies of some of the mutations have been performed and show that a reduction of human cardiac sodium current accounts for the pathogenesis of Brugada syndrome. Here we reported three novel SCN5A mutations identified in patients with Brugada syndrome in Taiwan (p.I848fs, p.R965C, and p.1876insM). Their electrophysiological properties were altered by patch clamp analysis. The p.I848fs mutant generated no sodium current. The p.R965C and p.1876insM mutants produced channels with steady state inactivation shifted to a more negative potential (9.4 mV and 8.5 mV respectively), and slower recovery from inactivation. Besides, the steady state activation of p.1876insM was altered and was shifted to a more positive potential (7.69 mV). In conclusion, the SCN5A channel defect related to Brugada syndrome might be diverse but all resulted in a decrease of sodium current.

Background SCN5A encodes the alpha subunit of human cardiac sodium channel, which is responsible for the generation of cardiac action potential and for rapid impulse conduc tion through the myocardium[1]. Mutations in SCN5A cause inherited arrthymia syndrome such as Long QT syn drome (LQT3), Brugada syndrome, isolated conduction disease, atrial stanstill, congenital sick sinus syndrome or

sudden infant death syndrome [2,3]. Chen et al. first reported in 1998 that loss of function mutations of SCN5A accounts for the most wellknown genetic basis for Brugada syndrom[4]. However, for the clinically diag nosed cases, only no more than 20% carry SCN5A muta tions[5]. Mutations in other genes that cause Brugada syndrome have been reported. These genes include glyc erol3phosphate dehydrogenase 1like gene (GPD1L),

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