Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA.
Department of Pathology, Orlando Health, Orlando, Florida, USA.
J Med Genet. 2022 Nov;59(11):1044-1057. doi: 10.1136/jmedgenet-2021-108115. Epub 2022 Feb 11.
Heterozygous loss of X-linked genes like 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. -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 -null mutation. We next generated a mouse line where is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.
The -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 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 deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of . Intriguingly, female mice with heterozygous deletion of in the cerebellum do not display neurodegeneration.
We suggest that X-linked neurodevelopmental disorders like 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.
X 连锁基因如 和 MeCP2（雷特综合征）的杂合性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。这些疾病的机制尚不清楚。X 连锁小脑发育不良被认为是由于 Tbr1- reelin 介导的神经元迁移缺陷所致。
我们在此报告一名 2 个月大死亡男婴的临床和组织病理学分析，该男婴携带 -null 突变。接下来，我们生成了一个在小脑中转录因子 Tbr1 缺失的小鼠模型。
-null 人类大脑体积较小，但分层正常，无神经元分化、迁移或轴突导向缺陷。发育后的小脑而非无脑则显示出星形胶质细胞和小胶质细胞增生，这是神经元丢失的标志物。因此，我们假设 缺失诱导的小脑发育不良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 缺失中，小脑体积较小是由于小脑颗粒神经元的发育后退化所致。此外，至少在小脑中， 缺失导致的功能丧失是颗粒细胞退化的结果，而不是由于 基因的急性分子功能丧失。有趣的是，小脑中携带 杂合缺失的雌性小鼠不显示神经退行性变。
我们认为 X 连锁神经发育障碍，如 突变和雷特综合征，在病理上是神经退行性的；杂合突变女孩中的随机 X 染色体失活导致 50%的细胞表达功能性基因，从而导致非进行性病理，而男孩中唯一等位基因的完全缺失导致不受限制的退化和脑病。
