Published Online
on September 17, 2009

This Article Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Mathur, N. Articles by Wehrens, X. H.T. PubMed Articles by Mathur, N. Articles by Wehrens, X. H.T. Related Collections Animal models of human disease Arrythmias-basic studies

Original Article

Sudden Infant Death Syndrome in Mice with an Inherited Mutation in RyR2

Nithin Mathur¹; Subeena Sood¹; Sufen Wang²; Ralph J. van Oort¹; Satyam Sarma¹; Na Li¹; Darlene G. Skapura¹; J. Henri Bayle¹; Miguel Valderrábano² and Xander H.T. Wehrens^1,3

¹ Baylor College of Medicine, Houston, TX;
² Methodist Hospital & Weill College of Medicine at Cornell University, Houston, TX

^* Corresponding author; email: wehrens{at}bcm.edu

Background—Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome (SIDS). The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice.

Methods and Results—Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type (WT) littermates. Optical mapping of membrane potentials and calcium levels in 1-7 day-old R176Q/+ and WT mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3-10 day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias following provocation with epinephrine and caffeine. Intracardiac pacing studies in 12-18 day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with WT mice. RT-PCR and Western blotting showed that expression levels of other calcium handling proteins were unaltered suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice.

Conclusions—Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice, and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with SIDS.

Key Words: arrhythmia • electrophysiology • ion channels • calcium • sudden infant death syndrome • focal activity • ryanodine receptors • ventricular arrhythmia