Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization
Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization
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DOI：
10.1212/nxg.0000000000000397
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发表时间：
2020-04-01
影响因子：
3.1
通讯作者：
Bird, Thomas D.
中科院分区：
文献类型：
--
作者：
Chen, Dong-Hui;Latimer, Caitlin;Bird, Thomas D.
目的探讨常染色体显性遗传性共济失调合并行为异常、认知功能下降和孤独症的遗传学病因，并探讨STUB 1相关性共济失调的脑神经病理特征及致病性变异对STUB 1定位的影响。在这些family. ResultsSTUB 1的突变主要与儿童发病的常染色体隐性共济失调，但在这里，我们报告杂合子错义变异STUB 1（p.Ile53Thr和p.The37Leu）确认常染色体显性遗传的最近报道的大脑进行了大体和显微神经病理学评价。小脑萎缩的影像学和认知功能障碍往往先于共济失调。对4只动物大脑进行的独特神经病理学检查显示浦肯野细胞（PC）明显丢失，小脑外无显著病理学的显微镜证据。极化体树突STUB 1蛋白在PC中的表达的正常模式丢失，导致异常的STUB 1本地化在远端PC树突arbors.ConclusionsThis研究证实了显性遗传模式的STUB 1-共济失调，除了一个隐性的和文件，其与认知和行为障碍，包括自闭症。在最广泛的分析小脑病理在这种疾病中，我们证明了中断的STUB 1蛋白在PC的一部分，潜在的发病机制。
ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.