Sudden infant death syndrome in mice with an inherited mutation in RyR2.
Sudden infant death syndrome in mice with an inherited mutation in RyR2.
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DOI：
10.1161/circep.109.894683
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Wehrens XH
中科院分区：
文献类型：
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作者：
Mathur N;Sood S;Wang S;van Oort RJ;Sarma S;Li N;Skapura DG;Bayle JH;Valderrábano M;Wehrens XH
心脏兰尼碱受体基因（RYR 2）的突变最近已被确定在婴儿猝死综合征（SIDS）的受害者。本研究的目的是确定RYR 2中的功能获得性突变是否会增加年轻小鼠心律失常和猝死的倾向。在Ryr 2中具有突变R176 Q（R176 Q/+）的杂合基因敲入小鼠中前瞻性地监测猝死的发生率。与野生型（WT）同窝仔相比，R176 Q/+幼龄小鼠的猝死发生率更高。1-7日龄R176 Q/+和WT小鼠的膜电位和钙水平的光学映射显示，新生R176 Q/+小鼠的心室异位和自发钙释放的发生率增加。3-10日龄小鼠的体表心电图显示，R176 Q/+小鼠在肾上腺素和咖啡因激发后发生更多的室性心律失常。在12-18日龄小鼠中进行的心内起搏研究显示，与WT小鼠相比，R176 Q/+中存在致瘤底物。RT-PCR和Western blotting显示其他钙处理蛋白的表达水平没有改变，这表明钙通过突变体RyR 2泄漏是年轻R176 Q/+小鼠中胚胎发生和猝死的基础。我们的研究结果表明，RyR 2的功能获得性突变使年轻小鼠心律失常和猝死的风险增加，年轻的R176 Q/+小鼠可用作阐明与SIDS相关的遗传和环境风险因素之间复杂相互作用的模型。
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. 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. 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.