Elucidation of pathological mechanism caused by human disease mutation in CaMKIIβ
Elucidation of pathological mechanism caused by human disease mutation in CaMKIIβ
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阐明人类疾病CaMKIIβ突变引起的病理机制
DOI：
10.1002/jnr.25013
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发表时间：
2022
影响因子：
4.2
通讯作者：
Saitsu H.
中科院分区：
文献类型：
--
作者：
Mutoh H;Aoto K;Miyazaki T;Fukuda A;Saitsu H.
最近，我们通过全外显子组测序研究发现了神经发育障碍患者中的CaMK II α和CaMK II β突变。使用细胞培养实验，大多数CaMKII突变体具有增加的Thr 286/287磷酸化，其诱导CaMKII的自主活性。在这项研究中，我们使用人类疾病的小鼠模型，探索了仅在CaMKIIβ中Pro213 Leu突变患者中观察到的运动功能障碍的病理机制。纯合子CaMKIIβ Pro213 Leu基因敲入小鼠从出生后2周开始表现出年龄依赖性运动功能障碍和生长衰竭。在小脑中，突变没有改变mRNA转录水平，但CaMK II β蛋白水平显著降低。此外，与先前来自细胞培养的结果相反，CaMKIIβ的Thr 287磷酸化也减少。CaMKIIβ Pro213 Leu敲入小鼠显示出与CaMKIIβ敲除小鼠相似的运动功能障碍，这为功能丧失而非功能获得提供了新的证据。我们的疾病模型小鼠表现出与患者相似的表型，除了癫痫发作。我们清楚地证明了病理机制是脑中突变型CaMKIIβ的减少，并且在体内和细胞培养之间突变的生理方面有很大不同。
Recently, we have identified CaMKIIα and CaMKIIβ mutations in patients with neurodevelopmental disorders by whole exome sequencing study. Most CaMKII mutants have increased phosphorylation of Thr286/287, which induces autonomous activity of CaMKII, using cell culture experiments. In this study, we explored the pathological mechanism of motor dysfunction observed exclusively in a patient with Pro213Leu mutation in CaMKIIβ using a mouse model of the human disease. The homozygous CaMKIIβ Pro213Leu knockin mice showed age‐dependent motor dysfunction and growth failure from 2 weeks after birth. In the cerebellum, the mutation did not alter the mRNA transcript level, but the CaMKIIβ protein level was dramatically decreased. Furthermore, in contrast to previous result from cell culture, Thr287 phosphorylation of CaMKIIβ was also reduced. CaMKIIβ Pro213Leu knockin mice showed similar motor dysfunction as CaMKIIβ knockout mice, newly providing evidence for a loss of function rather than a gain of function. Our disease model mouse showed similar phenotypes of the patient, except for epileptic seizures. We clearly demonstrated that the pathological mechanism is a reduction of mutant CaMKIIβ in the brain, and the physiological aspects of mutation were greatly different betweenin vivoand cell culture.
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影响因子：
56.9
作者：
CHEN, C;RAINNIE, DG;TONEGAWA, S
通讯作者：
TONEGAWA, S
CAMKIIβ 在调节皮质神经元迁移中的新作用：对神经发育障碍的影响
影响因子：
11
作者：
O. Nicole;Donald M. Bell;T. Leste;Hélène Doat;F. Guillemot;E. Pacary
通讯作者：
E. Pacary
影响因子：
9.8
作者：
Kury, Sebastien;van Woerden, Geeske M.;Mercier, Sandra
通讯作者：
Mercier, Sandra
影响因子：
5.3
作者：
Stephenson, Jason R.;Wang, Xiaohan;Colbran, Roger J.
通讯作者：
Colbran, Roger J.