Biallelic Variants in UBAS Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy
Biallelic Variants in UBAS Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy
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DOI：
10.1016/j.ajhg.2016.06.030
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发表时间：
2016-09-01
影响因子：
9.8
通讯作者：
Bonneau, Dominique
中科院分区：
文献类型：
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作者：
Colin, Estelle;Daniel, Jens;Bonneau, Dominique
通过全外显子组测序，我们确定了罕见的常染色体隐性变异的UBAS在五个孩子从四个不相关的家庭受到严重的智力缺陷，小头畸形，运动障碍，和/或早发性难治性癫痫的相似模式。UBA 5编码E1激活酶泛素折叠修饰物1（UFM 1），一种最近鉴定的泛素样蛋白。突变UBA 5蛋白的生化研究和受影响个体的成纤维细胞研究表明，UBA 5突变损害了ufmylation过程，导致异常内质网结构。在秀丽隐杆线虫中，UFM 1级联中的乌巴-5和人类orthogonal基因的敲除改变胆碱能神经传递，但不改变谷氨酸能神经传递。此外，斑马鱼的uba 5沉默降低了运动性，同时诱导了暗示癫痫发作的异常运动。这些临床、生化和实验研究结果支持我们的发现，即UBA 5突变是由于蛋白质异常ufmylation引起的早发性脑病的病理生理原因。
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBAS in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the El-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.