Department of Molecular Physiology and Biophysics, Division of Cardiology, Baylor College of Medicine, Houston, TX 77030, USA.
Circ Arrhythm Electrophysiol. 2009 Dec;2(6):677-85. doi: 10.1161/CIRCEP.109.894683.
Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. 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.
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 littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription-polymerase chain reaction 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.
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 sudden infant death syndrome.
心脏兰尼碱受体基因（RyR2）的突变最近在婴儿猝死综合征患者中被发现。本研究的目的是确定 RyR2 的功能获得性突变是否会增加年轻小鼠发生心律失常和猝死的倾向。
前瞻性监测具有 RyR2 突变 R176Q 的杂合敲入小鼠（R176Q/+）的猝死发生率。与野生型同窝仔相比，年轻的 R176Q/+ 小鼠猝死发生率更高。对 1-7 日龄 R176Q/+ 和野生型小鼠进行膜电位和细胞内钙的光学映射显示，新生 R176Q/+ 小鼠室性早搏和自发性钙释放的发生率增加。3-10 日龄小鼠的体表心电图显示，R176Q/+ 小鼠在给予肾上腺素和咖啡因刺激后更容易发生室性心律失常。12-18 日龄小鼠的心内起搏研究显示，与野生型相比，R176Q/+ 小鼠存在致心律失常的底物。逆转录-聚合酶链反应和 Western 印迹显示，其他钙处理蛋白的表达水平没有改变，这表明突变 RyR2 导致的钙漏是年轻 R176Q/+ 小鼠心律失常和猝死的基础。
我们的研究结果表明，RyR2 的功能获得性突变会增加年轻小鼠心律失常和猝死的风险，年轻的 R176Q/+ 小鼠可能被用作阐明与婴儿猝死综合征相关的遗传和环境风险因素之间复杂相互作用的模型。
