Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.
Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling.
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DOI：
10.14814/phy2.15265
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发表时间：
2022-04
影响因子：
2.5
通讯作者：
Gepstein, Lior
中科院分区：
文献类型：
--
作者：
Hopton, Claire;Tijsen, Anke J.;Maizels, Leonid;Arbel, Gil;Gepstein, Amira;Bates, Nicola;Brown, Benjamin;Huber, Irit;Kimber, Susan J.;Newman, William G.;Venetucci, Luigi;Gepstein, Lior
心脏ryanodine受体基因（RYR 2）的杂合错义变体可引起儿茶酚胺能多态性室性心动过速（CPVT）。RYR 2的这些错义变体导致兰尼碱受体的功能获得，其特征在于对钙激活的敏感性增加，导致产生钙波和延迟后去极化的倾向增加。我们最近在一名患有不明原因心脏骤停的年轻患者中检测到RYR 2的无意义变体。为了理解RYR 2中这种变体的机制，p。由于RYR 2中的新的无义变体（Arg 4790 Ter）导致室性心律失常，产生了在RYR 2中具有新的无义变体的人诱导多能干细胞（hiPSC）并分化成心肌细胞（RYR 2-hiPSC-CM），并研究了分子和钙处理特性。RYR 2-hiPSC-CM在基线和异丙肾上腺素治疗后显示出显著的钙处理异常。卡维地洛和奈必洛尔治疗导致RYR 2-hiPSC-CM中钙处理异常显著减少。在mRNA水平证实了突变RYR 2等位基因的表达，突变等位基因的部分沉默导致基线时钙处理异常减少。无义变体的行为类似于RYR 2中的其他功能变体的增益。卡维地洛和奈必洛尔可能是RYR 2变异体功能获得患者的合适治疗方法。RYR 2基因编码心肌兰尼碱受体，心肌细胞中的主要钙处理通道。RYR 2基因内的杂合变体引起遗传性心律失常综合征儿茶酚胺能多态性室性心动过速（CPVT）。这些变体中的大多数是错义变化，并通过功能机制的获得而导致表型。我们在心脏骤停的年轻女性中发现了RYR 2中的一种新的无义变体，并使用来自诱导多能干细胞的心肌细胞显示，该变体似乎以与先前描述的功能变体获得相似的机制导致异常钙处理。
Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2‐hiPSC‐CMs) and molecular and calcium handling properties were studied. RYR2‐hiPSC‐CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2‐hiPSC‐CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. The nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants. The RYR2 gene encodes for the cardiac ryanodine receptor, a major calcium handling channel in cardiomyocytes. Heterozygous variants within the RYR2 gene cause the inherited arrhythmia syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). The majority of these variants are missense changes and lead to a phenotype by a gain of function mechanism. We identified a novel nonsense variant in RYR2 in young women who suffered a cardiac arrest and show, using cardiomyocytes derived from induced pluripotent stem cells, that this variant appears to lead to abnormal calcium handling in a similar mechanism to the previously described gain of function variants.
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影响因子：
5.3
作者：
Novak A;Barad L;Lorber A;Gherghiceanu M;Reiter I;Eisen B;Eldor L;Itskovitz-Eldor J;Eldar M;Arad M;Binah O
通讯作者：
Binah O
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
37.8
作者：
LEENHARDT, A;LUCET, V;COUMEL, P
通讯作者：
COUMEL, P
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
5.9
作者：
Shinnawi, Rami;Huber, Irit;Gepstein, Lior
通讯作者：
Gepstein, Lior