Human Calmodulin Mutations.
Human Calmodulin Mutations.
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DOI：
10.3389/fnmol.2018.00396
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发表时间：
2018
影响因子：
4.8
通讯作者：
Overgaard MT
中科院分区：
文献类型：
--
作者：
Jensen HH;Brohus M;Nyegaard M;Overgaard MT
钙（Ca 2+）穿过细胞膜的流动使快速细胞反应成为可能。钙调素（CaM）感知局部Ca 2+浓度的变化，并将信息传递给众多的相互作用伙伴。在人类基因组中存在三个独立的CaM基因（CALM 1 -3），这一事实强调了准确的Ca 2+信号传导对细胞功能的关键作用。这三个基因都有功能，编码完全相同的CaM蛋白。此外，CaM在所有脊椎动物中具有完全保守的氨基酸序列。鉴于这种保守程度，人们长期认为CaM的突变与生命不相容。因此，当六年前发现人类中的第一个CaM突变时，这是一个很大的惊喜。今天，已经描述了十几种人类CaM错义突变，所有这些突变都在严重心律失常患者中发现。生物化学研究表明，这些钙调素变体的钙离子结合亲和力的差异影响。此外，中央心脏离子通道的CaM调节受损，包括电压门控Ca 2+通道CaV1.2和肌浆网Ca 2+释放通道Ryanodine受体亚型2 RyR 2。目前，没有非心脏表型已被描述为钙调素变异载体。然而，大型人类队列的测序揭示了额外的罕见CaM突变的累积频率，这些突变增加了CaM变体不完全引起严重心律失常的可能性。在这里，我们提供了一个概述的钙调素变异及其已知的后果，为目标的调节和心脏疾病的表型。我们讨论了实验数据，患者的基因型和表型，以及哪些问题仍然是开放的，以了解这种复杂性。
Fluxes of calcium (Ca2+) across cell membranes enable fast cellular responses. Calmodulin (CaM) senses local changes in Ca2+ concentration and relays the information to numerous interaction partners. The critical role of accurate Ca2+ signaling on cellular function is underscored by the fact that there are three independent CaM genes (CALM1-3) in the human genome. All three genes are functional and encode the exact same CaM protein. Moreover, CaM has a completely conserved amino acid sequence across all vertebrates. Given this degree of conservation, it was long thought that mutations in CaM were incompatible with life. It was therefore a big surprise when the first CaM mutations in humans were identified six years ago. Today, more than a dozen human CaM missense mutations have been described, all found in patients with severe cardiac arrhythmias. Biochemical studies have demonstrated differential effects on Ca2+ binding affinities for these CaM variants. Moreover, CaM regulation of central cardiac ion channels is impaired, including the voltage-gated Ca2+ channel, CaV1.2, and the sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor isoform 2, RyR2. Currently, no non-cardiac phenotypes have been described for CaM variant carriers. However, sequencing of large human cohorts reveals a cumulative frequency of additional rare CaM mutations that raise the possibility of CaM variants not exclusively causing severe cardiac arrhythmias. Here, we provide an overview of the identified CaM variants and their known consequences for target regulation and cardiac disease phenotype. We discuss experimental data, patient genotypes and phenotypes as well as which questions remain open to understand this complexity.
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与长QT综合征相关的钙调蛋白突变可防止心脏L型Ca（2+）电流失活，并促进心室心肌细胞中心律失常。
影响因子：
5
作者：
Limpitikul, Worawan B.;Dick, Ivy E.;Joshi-Mukherjee, Rosy;Overgaard, Michael T.;George, Alfred L., Jr.;Yue, David T.
通讯作者：
Yue, David T.
DOI：
10.1161/circep.116.004161
发表时间：
2016-08
期刊：
Circulation. Arrhythmia and electrophysiology
影响因子：
--
作者：
Gomez-Hurtado N;Boczek NJ;Kryshtal DO;Johnson CN;Sun J;Nitu FR;Cornea RL;Chazin WJ;Calvert ML;Tester DJ;Ackerman MJ;Knollmann BC
通讯作者：
Knollmann BC
影响因子：
20.1
作者：
Limpitikul WB;Dick IE;Tester DJ;Boczek NJ;Limphong P;Yang W;Choi MH;Babich J;DiSilvestre D;Kanter RJ;Tomaselli GF;Ackerman MJ;Yue DT
通讯作者：
Yue DT
影响因子：
7
作者：
O'Connell, David J.;Bauer, Mikael C.;Cahill, Dolores J.
通讯作者：
Cahill, Dolores J.
影响因子：
3.9
作者：
KRETSINGER, RH;RUDNICK, SE;WEISSMAN, LJ
通讯作者：
WEISSMAN, LJ