From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan.
Neurology. 2014 Oct 21;83(17):1554-61. doi: 10.1212/WNL.0000000000000909. Epub 2014 Sep 24.
To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort.
Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs.
Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6.
SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.
阐明由转谷氨酰胺酶 6（TG6）编码基因 TGM6 突变引起的脊髓小脑共济失调 35 型（SCA35）的临床和细胞学特征。
在排除了 15 种其他共济失调综合征相关突变的情况下，对来自 512 个家系的 109 名汉族无关 SCA 先证者分子未明确的患者进行 TGM6 基因突变检测。系统分析所有 TGM6 突变患者的临床特征。使用突变互补 DNA 构建体转染 HEK293 细胞，研究新鉴定的 TGM6 突变的生物学后果。
鉴定出 TGM6 中的 2 个错义突变（p.R111C 和 p.D510H）和 1 个 3 碱基对缺失（p.E574del）。其中，p.R111C 和 p.E574del 是新发现的。SCA35 的共同特征包括进展缓慢的临床病程、躯干/肢体共济失调和手部震颤。发病年龄从青少年到五十岁不等。斜颈和智力障碍是罕见的表现。脑 MRI 显示弥漫性小脑萎缩，不涉及大脑半球或脑干。本研究中鉴定的 3 种突变降低了 TG6 的蛋白稳定性和催化活性。
SCA35 是一种不常见的共济失调综合征，在台湾汉族人群中的发病率为 0.6%（3/512）。本研究扩展了 SCA35 的突变谱，并强调了 TG6 在小脑功能中的重要性。
