Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction

Yutao Xi, Tomohiko Ai, Enno De Lange, Zhaohui Li, Geru Wu, Luca Brunelli, W. Buck Kyle, Isik Turker, Jie Cheng, Michael J. Ackerman, Akinori Kimura, James N. Weiss, Zhilin Qu, Jeffrey J. Kim, Georgine Faulkner, Matteo Vatta

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Background - Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM-001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Nav1.5) that plays an important role in the cardiac conduction system. Methods and Results - Effects of ZASP1-wild-type and ZASP1-D117N on Nav1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated INa by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Nav1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Nav1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1- sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Nav1.5. Conclusions - ZASP1 can form protein complex with telethonin/T-Cap and Nav1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na v1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Nav1.5.

Original languageEnglish (US)
Pages (from-to)1017-1026
Number of pages10
JournalCirculation: Arrhythmia and Electrophysiology
Volume5
Issue number5
DOIs
StatePublished - Oct 1 2012

Keywords

  • Cardiac conduction disturbance
  • Left ventricular noncompaction
  • Sodium channel
  • Z-band alternatively spliced PDZ motif gene

ASJC Scopus subject areas

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

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    Xi, Y., Ai, T., De Lange, E., Li, Z., Wu, G., Brunelli, L., Kyle, W. B., Turker, I., Cheng, J., Ackerman, M. J., Kimura, A., Weiss, J. N., Qu, Z., Kim, J. J., Faulkner, G., & Vatta, M. (2012). Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction. Circulation: Arrhythmia and Electrophysiology, 5(5), 1017-1026. https://doi.org/10.1161/CIRCEP.111.969220