Chen Dong-Hui, Latimer Caitlin, Yagi Mayumi, Ndugga-Kabuye Mesaki Kenneth, Heigham Elyana, Jayadev Suman, Meabon James S, Gomez Christopher M, Keene C Dirk, Cook David G, Raskind Wendy H, Bird Thomas D
Department of Neurology (D.-H.C., E.H., S.J., T.D.B.), University of Washington, Seattle; Department of Pathology (C.L., C.D.K.), Neuropathology Division, University of Washington, Seattle; Geriatric Research, Education, and Clinical Center (GRECC) (M.Y., D.G.C., W.H.R., T.D.B.), VA Puget Sound Health Care System, Seattle, WA; Department of Medicine (M.K.N.-K., W.H.R., T.D.B.), Division of Medical Genetics, University of Washington, Seattle; Mental Illness Research, Education, and Clinical Center (MIRECC) (J.S.M., W.H.R.), VA Puget Sound Health Care System, Seattle, WA; Department of Psychiatry and Behavioral Sciences (J.S.M., W.H.R.), University of Washington, Seattle; Department of Neurology (C.M.G.), University of Chicago, IL; Department of Medicine (D.G.C.), Division of Gerontology and Geriatric Medicine, University of Washington, Seattle; and Department of Pharmacology (D.G.C.), University of Washington, Seattle.
Neurol Genet. 2020 Feb 10;6(2):1-13. doi: 10.1212/NXG.0000000000000397. eCollection 2020 Apr.
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 -related ataxia and investigate the effects of pathogenic variants on 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 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in (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 -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.
确定两个家族中常染色体显性共济失调合并行为异常、认知衰退和自闭症的遗传原因，描绘显性相关共济失调的脑病理特征，并研究致病变异对定位的影响。
采用基于临床和研究的外显子组测序来确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大体和显微镜下的神经病理学评估。
突变主要与儿童期发病的常染色体隐性共济失调相关，但在此我们报告了中的杂合错义变异（p.Ile53Thr和p.The37Leu），证实了最近关于常染色体显性遗传的报道。影像学上的小脑萎缩和认知缺陷通常先于共济失调出现。对4个大脑进行的独特神经病理学检查显示，浦肯野细胞（PCs）明显丢失，而小脑外无明显病理的显微镜证据。PCs中极化的体树突状STUB1蛋白表达的正常模式丧失，导致STUB1在PC远端树突分支中异常定位。
本研究证实了-共济失调除隐性遗传模式外的显性遗传模式，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的最广泛分析中，我们证明PCs中STUB1蛋白的破坏是潜在发病机制的一部分。
