UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.
UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.
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UBA5突变导致一种新形式的常染色体隐性小脑性共济失调
DOI：
10.1371/journal.pone.0149039
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Tang B
中科院分区：
文献类型：
--
作者：
Duan R;Shi Y;Yu L;Zhang G;Li J;Lin Y;Guo J;Wang J;Shen L;Jiang H;Wang G;Tang B
常染色体隐性遗传小脑性共济失调（ARCA）包括一个大的和异质性的神经退行性疾病组。对于许多受影响的患者来说，遗传原因仍然无法确定。通过全外显子组测序，我们确定了两个中国同胞的ARCA的泛素样修饰物激活酶5基因（UBA 5）的复合杂合突变。此外，在ClinVar数据库中记录了UBA 5或泛素折叠修饰因子1基因（UFM 1）的拷贝数变异与整体发育迟缓和步态障碍的表型。UBA 5编码UBA 5，UFM 1的泛素激活酶。然而，UBA 5在人类神经系统疾病中的关键作用仍有待报道。我们对UBA 5-R246 X的分子研究显示，由于缺乏催化性半胱氨酸Cys 250，UFM 1的半衰期显著缩短，并且失去了UFM 1的活化。UBA 5-K310 E保持了与UFM 1的相互作用，但稳定性较低，这可能影响该UBA 5突变体激活UFM 1的能力。果蝇模型显示，UBA 5敲低诱导运动缺陷和缩短的寿命伴随着异常的神经肌肉接头（NMJ）。引人注目的是，我们发现UFM 1和E2辅因子敲低诱导了明显相似的表型。野生型UBA 5，而不是突变体UBA 5，显着恢复由UBA 5的缺乏引起的神经病变。小脑性共济失调中UBA 5突变的发现表明UFM 1通路的损伤可能有助于ARCA的神经学表型。
Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA.