Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.
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DOI：
10.1093/brain/awy135
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
作者：
Nahorski MS;Maddirevula S;Ishimura R;Alsahli S;Brady AF;Begemann A;Mizushima T;Guzmán-Vega FJ;Obata M;Ichimura Y;Alsaif HS;Anazi S;Ibrahim N;Abdulwahab F;Hashem M;Monies D;Abouelhoda M;Meyer BF;Alfadhel M;Eyaid W;Zweier M;Steindl K;Rauch A;Arold ST;Woods CG;Komatsu M;Alkuraya FS
Ufmylation是通过添加UFM 1对蛋白质进行的翻译后修饰。Nahorksi等人在患有严重早发性脑病伴进行性小头畸形的个体中鉴定了UFM 1和UFC 1的突变，UFC 1编码ufmylation所需的酶。这些发现表明ufmylation在人类大脑发育中起着重要作用。通过添加UFM 1对蛋白质进行翻译后修饰，也称为ufmylation，在动物模型研究中显示，这种修饰在发育中起着关键作用。最近发现UBA 5（Ufmylation的E1样酶）的双等位基因突变导致严重的早发性脑病伴进行性小头畸形，这暗示了Ufmylation在人脑发育中的作用。最近，一种纯合子UFM 1变异被认为是严重早发性脑病伴进行性小头畸形的候选病因。在这里，我们建立了一个严重的早发性脑病进行性小头畸形的基因座的基础上两个家庭，并映射表型的一种新的纯合UFM 1突变。该突变具有显著降低的与UBA 5和UFC 1（用于ufmylation的E2样酶）形成硫酯中间体的能力，导致细胞蛋白的ufmylation受损。值得注意的是，在另外四个家庭中，其中八名儿童患有严重的早发性脑病伴进行性小头畸形，我们确定了两个双等位基因UFC 1突变，这会损害UFM 1-UFC 1中间体的形成，导致细胞ufmylation的广泛减少，这与UFM 1突变观察到的模式相似。UFM 1和UFC 1相关的临床表型和生化紊乱之间的惊人相似性强烈地支持ufmylation在人脑发育中的重要作用。UFM 1和UFC 1突变的亚型性质和在人类基因组数据库中该途径的组分中双等位基因无效突变的明显耗尽表明，这对于胚胎存活是必要的，这与敲除模型的胚胎致死性质一致。
Ufmylation is the post-translational modification of proteins through the addition of UFM1. Nahorksi et al. identify mutations in UFM1 and in UFC1, which encodes an enzyme required for ufmylation, in individuals with severe early-onset encephalopathy with progressive microcephaly. The findings suggest an essential role for ufmylation in human brain development. The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.
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影响因子：
62.1
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
9.8
作者：
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通讯作者：
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