A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy

Zhaohui Li, Tomohiko Ai, Kaveh Samani, Yutao Xi, Huei Ping Tzeng, Mingxing Xie, Shan Wu, Shuping Ge, Michael D. Taylor, Jian Wen Dong, Jie Cheng, Michael J. Ackerman, Akinori Kimura, Gianfranco Sinagra, Luca Brunelli, Georgine Faulkner, Matteo Vatta

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background-Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. Methods and Results-We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and proteinprotein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca2+ currents and Na+ currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca v1.2) and sodium (Nav1.5) channels. Conclusions-Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.

Original languageEnglish
Pages (from-to)646-656
Number of pages11
JournalCirculation: Arrhythmia and Electrophysiology
Volume3
Issue number6
DOIs
StatePublished - Dec 2010

Fingerprint

Dilated Cardiomyopathy
Missense Mutation
Cardiomyopathies
Sudden Cardiac Death
Mutation
Cardiac Myocytes
Cardiac Arrhythmias
Cytoskeletal Proteins
Atrioventricular Block
Sodium Channels
Heart Arrest
Ion Channels
Tachycardia
Transgenic Mice
Exons
Myocardium
Hemodynamics
Calcium

Keywords

  • ACTN2
  • Arrhythmias
  • Ca1.2
  • Conduction
  • DCM
  • Na1.5
  • Telethonin
  • ZASP

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Medicine(all)

Cite this

A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. / Li, Zhaohui; Ai, Tomohiko; Samani, Kaveh; Xi, Yutao; Tzeng, Huei Ping; Xie, Mingxing; Wu, Shan; Ge, Shuping; Taylor, Michael D.; Dong, Jian Wen; Cheng, Jie; Ackerman, Michael J.; Kimura, Akinori; Sinagra, Gianfranco; Brunelli, Luca; Faulkner, Georgine; Vatta, Matteo.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 3, No. 6, 12.2010, p. 646-656.

Research output: Contribution to journalArticle

Li, Z, Ai, T, Samani, K, Xi, Y, Tzeng, HP, Xie, M, Wu, S, Ge, S, Taylor, MD, Dong, JW, Cheng, J, Ackerman, MJ, Kimura, A, Sinagra, G, Brunelli, L, Faulkner, G & Vatta, M 2010, 'A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy', Circulation: Arrhythmia and Electrophysiology, vol. 3, no. 6, pp. 646-656. https://doi.org/10.1161/CIRCEP.109.929240
Li, Zhaohui ; Ai, Tomohiko ; Samani, Kaveh ; Xi, Yutao ; Tzeng, Huei Ping ; Xie, Mingxing ; Wu, Shan ; Ge, Shuping ; Taylor, Michael D. ; Dong, Jian Wen ; Cheng, Jie ; Ackerman, Michael J. ; Kimura, Akinori ; Sinagra, Gianfranco ; Brunelli, Luca ; Faulkner, Georgine ; Vatta, Matteo. / A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. In: Circulation: Arrhythmia and Electrophysiology. 2010 ; Vol. 3, No. 6. pp. 646-656.
@article{525e22bbe75f4f879540c64fa2ae568d,
title = "A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy",
abstract = "Background-Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. Methods and Results-We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and proteinprotein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca2+ currents and Na+ currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca v1.2) and sodium (Nav1.5) channels. Conclusions-Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.",
keywords = "ACTN2, Arrhythmias, Ca1.2, Conduction, DCM, Na1.5, Telethonin, ZASP",
author = "Zhaohui Li and Tomohiko Ai and Kaveh Samani and Yutao Xi and Tzeng, {Huei Ping} and Mingxing Xie and Shan Wu and Shuping Ge and Taylor, {Michael D.} and Dong, {Jian Wen} and Jie Cheng and Ackerman, {Michael J.} and Akinori Kimura and Gianfranco Sinagra and Luca Brunelli and Georgine Faulkner and Matteo Vatta",
year = "2010",
month = "12",
doi = "10.1161/CIRCEP.109.929240",
language = "English",
volume = "3",
pages = "646--656",
journal = "Circulation: Arrhythmia and Electrophysiology",
issn = "1941-3149",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy

AU - Li, Zhaohui

AU - Ai, Tomohiko

AU - Samani, Kaveh

AU - Xi, Yutao

AU - Tzeng, Huei Ping

AU - Xie, Mingxing

AU - Wu, Shan

AU - Ge, Shuping

AU - Taylor, Michael D.

AU - Dong, Jian Wen

AU - Cheng, Jie

AU - Ackerman, Michael J.

AU - Kimura, Akinori

AU - Sinagra, Gianfranco

AU - Brunelli, Luca

AU - Faulkner, Georgine

AU - Vatta, Matteo

PY - 2010/12

Y1 - 2010/12

N2 - Background-Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. Methods and Results-We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and proteinprotein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca2+ currents and Na+ currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca v1.2) and sodium (Nav1.5) channels. Conclusions-Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.

AB - Background-Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. Methods and Results-We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and proteinprotein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca2+ currents and Na+ currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca v1.2) and sodium (Nav1.5) channels. Conclusions-Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM.

KW - ACTN2

KW - Arrhythmias

KW - Ca1.2

KW - Conduction

KW - DCM

KW - Na1.5

KW - Telethonin

KW - ZASP

UR - http://www.scopus.com/inward/record.url?scp=79952118916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952118916&partnerID=8YFLogxK

U2 - 10.1161/CIRCEP.109.929240

DO - 10.1161/CIRCEP.109.929240

M3 - Article

VL - 3

SP - 646

EP - 656

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

SN - 1941-3149

IS - 6

ER -