Abstract：
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 postmigratory 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, which are markers for neuronal loss. We therefore hypothesise 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 postdevelopmental degeneration of cerebellar granule neurons. Furthermore, 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.
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 postmigratory 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, which are markers for neuronal loss. We therefore hypothesise 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 postdevelopmental degeneration of cerebellar granule neurons. Furthermore, 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.
摘要：
X连锁基因如CASK和MeCP2（Rett综合征）的杂合缺失会导致女孩发育迟缓，而在男孩，这些基因唯一等位基因的缺失导致癫痫性脑病。这些疾病的机制仍然未知。CASK相关的小脑发育不全被认为是由Tbr1-reelin介导的神经元迁移缺陷引起的。
在这里，我们报告了一个具有CASK无效突变的2个月大男孩的临床和组织病理学分析。接下来，我们产生了一个小鼠系，其中CASK从小脑的迁移后神经元中完全缺失（半合子和纯合）。
无CASK的人脑尺寸较小，但表现出正常的分层，没有缺陷的神经元分化，迁移或轴突引导。发育不良的小脑反而表现为星形胶质细胞增生和小胶质细胞增生，它们是神经元丢失的标记。因此，我们假设CASK丢失引起的小脑发育不全是早期神经变性的结果。来自小鼠模型的数据证实，在CASK丢失中，小脑是由小脑颗粒神经元发育后变性引起的。此外，至少在小脑,CASK缺失的功能丧失是颗粒细胞变性的继发原因，而不是由于CASK的急性分子功能丧失。有趣的是，小脑中CASK杂合缺失的雌性小鼠不显示神经变性。
我们认为，像CASK突变和Rett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；杂合突变女孩的随机X染色体失活，然而,导致50%的细胞表达功能基因，导致非进行性病理学，而男孩中唯一等位基因的完全丢失会导致不受约束的变性和脑病。
在这里，我们报告了一个具有CASK无效突变的2个月大男孩的临床和组织病理学分析。接下来，我们产生了一个小鼠系，其中CASK从小脑的迁移后神经元中完全缺失（半合子和纯合）。
无CASK的人脑尺寸较小，但表现出正常的分层，没有缺陷的神经元分化，迁移或轴突引导。发育不良的小脑反而表现为星形胶质细胞增生和小胶质细胞增生，它们是神经元丢失的标记。因此，我们假设CASK丢失引起的小脑发育不全是早期神经变性的结果。来自小鼠模型的数据证实，在CASK丢失中，小脑是由小脑颗粒神经元发育后变性引起的。此外，至少在小脑,CASK缺失的功能丧失是颗粒细胞变性的继发原因，而不是由于CASK的急性分子功能丧失。有趣的是，小脑中CASK杂合缺失的雌性小鼠不显示神经变性。
我们认为，像CASK突变和Rett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；杂合突变女孩的随机X染色体失活，然而,导致50%的细胞表达功能基因，导致非进行性病理学，而男孩中唯一等位基因的完全丢失会导致不受约束的变性和脑病。
