To 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.

Clinical 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.

Mutations 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.

This 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.

旨在确定 2 个家族中常染色体显性共济失调并发行为异常、认知衰退和自闭症的遗传原因，并表征显性STUB1相关共济失调的脑神经病理学特征，并研究致病性变异对STUB1定位的影响。

使用基于临床和研究的外显子组测序来鉴定两个家族中常染色体显性共济失调的致病变异。对这些家族中 4 名受影响个体的大脑进行了肉眼和显微镜神经病理学评估。

STUB1突变主要与儿童期发病的常染色体隐性共济失调有关，但在这里我们报告了STUB1的杂合错义变异（p.Ile53Thr 和 p.The37Leu），证实了最近关于常染色体显性遗传的报道。影像学和认知缺陷的小脑萎缩通常先于共济失调。对 4 个大脑进行的独特神经病理学检查显示浦肯野细胞 (PC) 显着丧失，但小脑外没有显着病理的显微镜证据。 PC 中极化体细胞树突 STUB1 蛋白表达的正常模式丢失，导致 PC 远端树突轴中 STUB1 定位异常。

这项研究证实了STUB1共济失调除了隐性遗传模式之外还存在显性遗传模式，并记录了其与认知和行为障碍（包括自闭症）的关联。在对该疾病小脑病理学最广泛的分析中，我们证明 PC 中 STUB1 蛋白的破坏是潜在发病机制的一部分。