Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density

Cheng Shen, Lei Xu, Shasha Han, Zhen Dong, Xiaona Zhao, Shaochun Wang, Sanli Qian, Bingyu Li, Xin Ma, Peng Wang, Hong Zhu, Yunzeng Zou, Zheng Fan, Junbo Ge, Aijun Sun

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background Variants of SCN5A, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel SCN5A variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM. Methods SCN5A exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition. Results We found three novel non-synonymous SCN5A variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCMrelated variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages. Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.

Original languageEnglish (US)
Pages (from-to)762-770
Number of pages9
JournalJournal of medical genetics
Volume54
Issue number11
DOIs
StatePublished - Nov 1 2017

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Dilated Cardiomyopathy
Sodium
Atrioventricular Node
Atrioventricular Block
Sodium Channels
Homologous Recombination
Cardiac Myocytes
Cardiac Arrhythmias
Inpatients
Exons
Electrocardiography
Phenotype
Incidence
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density. / Shen, Cheng; Xu, Lei; Han, Shasha; Dong, Zhen; Zhao, Xiaona; Wang, Shaochun; Qian, Sanli; Li, Bingyu; Ma, Xin; Wang, Peng; Zhu, Hong; Zou, Yunzeng; Fan, Zheng; Ge, Junbo; Sun, Aijun.

In: Journal of medical genetics, Vol. 54, No. 11, 01.11.2017, p. 762-770.

Research output: Contribution to journalArticle

Shen, C, Xu, L, Han, S, Dong, Z, Zhao, X, Wang, S, Qian, S, Li, B, Ma, X, Wang, P, Zhu, H, Zou, Y, Fan, Z, Ge, J & Sun, A 2017, 'Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density', Journal of medical genetics, vol. 54, no. 11, pp. 762-770. https://doi.org/10.1136/jmedgenet-2017-104780
Shen, Cheng ; Xu, Lei ; Han, Shasha ; Dong, Zhen ; Zhao, Xiaona ; Wang, Shaochun ; Qian, Sanli ; Li, Bingyu ; Ma, Xin ; Wang, Peng ; Zhu, Hong ; Zou, Yunzeng ; Fan, Zheng ; Ge, Junbo ; Sun, Aijun. / Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density. In: Journal of medical genetics. 2017 ; Vol. 54, No. 11. pp. 762-770.
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abstract = "Background Variants of SCN5A, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel SCN5A variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM. Methods SCN5A exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition. Results We found three novel non-synonymous SCN5A variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCMrelated variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages. Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.",
author = "Cheng Shen and Lei Xu and Shasha Han and Zhen Dong and Xiaona Zhao and Shaochun Wang and Sanli Qian and Bingyu Li and Xin Ma and Peng Wang and Hong Zhu and Yunzeng Zou and Zheng Fan and Junbo Ge and Aijun Sun",
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T1 - Novel idiopathic DCM-related SCN5A variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density

AU - Shen, Cheng

AU - Xu, Lei

AU - Han, Shasha

AU - Dong, Zhen

AU - Zhao, Xiaona

AU - Wang, Shaochun

AU - Qian, Sanli

AU - Li, Bingyu

AU - Ma, Xin

AU - Wang, Peng

AU - Zhu, Hong

AU - Zou, Yunzeng

AU - Fan, Zheng

AU - Ge, Junbo

AU - Sun, Aijun

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Background Variants of SCN5A, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel SCN5A variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM. Methods SCN5A exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition. Results We found three novel non-synonymous SCN5A variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCMrelated variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages. Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.

AB - Background Variants of SCN5A, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel SCN5A variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM. Methods SCN5A exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition. Results We found three novel non-synonymous SCN5A variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCMrelated variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages. Conclusion Our results suggest that the iDCM-related SCN5A variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.

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U2 - 10.1136/jmedgenet-2017-104780

DO - 10.1136/jmedgenet-2017-104780

M3 - Article

VL - 54

SP - 762

EP - 770

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 11

ER -