Complete loss of the X-linked gene CASK causes severe cerebellar degeneration.
Complete loss of the X-linked gene CASK causes severe cerebellar degeneration.
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DOI：
10.1136/jmedgenet-2021-108115
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发表时间：
2022-11
影响因子：
4
通讯作者：
中科院分区：
文献类型：
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X连锁基因（如CASK和MeCP2，后者与瑞特综合征有关）杂合缺失会导致女孩发育迟缓，而在男孩中，这些基因的唯一等位基因缺失会导致癫痫性脑病。这些疾病的发病机制尚不清楚。与CASK相关的小脑发育不全被推测是由Tbr1 - 瑞林介导的神经元迁移缺陷所致。
在此我们报告了一名患有CASK无效突变的2个月大死亡男婴的临床和组织病理学分析。接下来我们培育了一个小鼠品系，其中小脑迁移后神经元中的CASK完全缺失（半合子和纯合子缺失）。
CASK缺失的人脑体积较小，但呈现正常的分层，没有神经元分化、迁移或轴突导向缺陷。发育不全的小脑反而表现出星形胶质细胞增生和小胶质细胞增生，这是神经元缺失的标志。因此我们假设CASK缺失导致的小脑发育不全是早期神经退行性变的结果。来自小鼠模型的数据证实，在CASK缺失的情况下，小脑体积小是由小脑颗粒神经元在发育后的退化所致。此外，至少在小脑中，CASK缺失导致的功能丧失是颗粒细胞退化的结果，而非CASK急性分子功能丧失所致。有趣的是，小脑中CASK杂合缺失的雌性小鼠没有表现出神经退行性变。
我们认为，像CASK突变和瑞特综合征这样的X连锁神经发育障碍在病理上是神经退行性的；然而，杂合突变女孩中随机的X染色体失活导致50%的细胞表达功能基因，从而产生非进行性病理，而男孩中唯一等位基因的完全缺失导致无限制的退化和脑病。
CASK缺失导致小脑退化。
Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration. Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from post-migratory neurons in the cerebellum. The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration, or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, markers for neuronal loss. We therefore hypothesize that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from post-developmental degeneration of cerebellar granule neurons. Further, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration. We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy. CASK loss causes cerebellar degeneration.
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DOI：
10.1083/jcb.200712094
发表时间：
2008-07-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chao HW;Hong CJ;Huang TN;Lin YL;Hsueh YP
通讯作者：
Hsueh YP
影响因子：
30.8
作者：
HIROTSUNE, S;TAKAHARA, T;HAYASHIZAKI, Y
通讯作者：
HAYASHIZAKI, Y
影响因子：
16.2
作者：
Hevner, RF;Shi, LM;Rubenstein, JLR
通讯作者：
Rubenstein, JLR
影响因子：
3.7
作者：
Burglen L;Chantot-Bastaraud S;Garel C;Milh M;Touraine R;Zanni G;Petit F;Afenjar A;Goizet C;Barresi S;Coussement A;Ioos C;Lazaro L;Joriot S;Desguerre I;Lacombe D;des Portes V;Bertini E;Siffroi JP;de Villemeur TB;Rodriguez D
通讯作者：
Rodriguez D
影响因子：
11
作者：
Gao R;Piguel NH;Melendez-Zaidi AE;Martin-de-Saavedra MD;Yoon S;Forrest MP;Myczek K;Zhang G;Russell TA;Csernansky JG;Surmeier DJ;Penzes P
通讯作者：
Penzes P