Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk

Hassan Musa, Cherisse A. Marcou, Todd J. Herron, Michael A. Makara, David J. Tester, Ryan P. O'Connell, Brad Rosinski, Guadalupe Guerrero-Serna, Michelle L. Milstein, André Monteiro Da Rocha, Dan Ye, Lia Crotti, Vladislav V. Nesterenko, Silvia Castelletti, Margherita Torchio, Maria Christina Kotta, Federica Dagradi, Charles Antzelevitch, Peter J. Mohler, Peter J. SchwartzMichael J. Ackerman, Justus M. Anumonwo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk. Am J Physiol Heart Circ Physiol 318: H1357-H1370, 2020. First published March 20, 2020; doi:10.1152/ajpheart.00481.2019.-Synapseassociated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiactargeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiacspecific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (Ito) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease.

Original languageEnglish (US)
Pages (from-to)H1357-H1370
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume318
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • Sap97
  • arrhythmia
  • ion channels

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk'. Together they form a unique fingerprint.

Cite this