Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy
Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy
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DOI：
10.1016/j.ajhg.2016.08.005
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发表时间：
2016-10-06
影响因子：
9.8
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Miyake, Noriko;Fukai, Ryoko;Matsumoto, Naomichi
我们描述了四个家庭的受影响的兄弟姐妹表现出独特的临床特征：早发性（1岁之前）进行性弥漫性脑萎缩与回归，出生后小头畸形，出生后生长迟缓，肌无力/萎缩，呼吸衰竭。通过全外显子组测序，我们在来自四个家族的八个受影响的个体中鉴定了双等位基因TBCD突变。TBCD编码TBCD（微管蛋白折叠辅因子D），其是在所有细胞中的微管组装中起关键作用的五种微管蛋白特异性伴侣之一。共发现7个突变：5个错义突变，1个无义突变和1个剪接位点突变导致移码。体外细胞实验显示，大多数突变TBCD蛋白与ARL 2、TBCE和J3-微管蛋白之间的结合受损。使用果蝇嗅觉投射神经元的体内实验表明，TBCD突变导致功能丧失。在这种神经退行性脑病中观察到的广泛的临床严重程度可能是由突变TBCD蛋白的残余功能引起的。此外，一名死者的尸检大脑显示出特征性的神经变性发现：小脑中残留的浦肯野细胞中的仙人掌和体芽形成，这也见于与线粒体损伤相关的一些疾病。TBCD突变引起的微管形成缺陷可能是这种神经退行性脑病的病理机制之一。
We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frame shift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and J3-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.