A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy
A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy
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DOI：
10.1136/jmedgenet-2019-106496
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发表时间：
2020-12-01
影响因子：
4
通讯作者：
Ravenscroft, Gina
中科院分区：
文献类型：
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作者：
Cabrera-Serrano, Macarena;Coote, David Joseph;Ravenscroft, Gina
背景duba5是UFM1在ufmyation翻译后修饰系统中的激活酶。不同的神经系统表型与UBA5致病变异相关，包括癫痫、智力残疾、运动障碍和共济失调。方法和结果我们描述了一个大的多代近亲家庭表现出严重的先天性神经病变，导致婴儿早期死亡。全外显子组测序和连锁分析鉴定出一种新的纯合子UBA5 NM_024818.3 c.31C>T （p.a r11trp）突变。小鼠组织中的蛋白表达分析显示，周围神经和中枢神经系统中的UBA5水平相似。与野生型相比，经过CRISPR-Cas9编辑的UBA5 p.a arg11trp突变纯合的HEK（人胚胎肾）细胞显示UBA5蛋白水平降低。突变体p.a arg11trp UBA5蛋白显示出激活UFM1的能力降低。结论本报告扩大了UBA5突变的表型谱，包括致死性周围神经病变。
BackgroundUBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia.Methods and resultsWe describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM_024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1.ConclusionThis report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy.