UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.
UFM1 founder mutation in the Roma population causes recessive variant of H-ABC.
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DOI：
10.1212/wnl.0000000000004578
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发表时间：
2017-10-24
期刊：
影响因子：
9.9
通讯作者：
Recessive H-ABC Research Group
中科院分区：
文献类型：
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作者：
Hamilton EMC;Bertini E;Kalaydjieva L;Morar B;Dojčáková D;Liu J;Vanderver A;Curiel J;Persoon CM;Diodato D;Pinelli L;van der Meij NL;Plecko B;Blaser S;Wolf NI;Waisfisz Q;Abbink TEM;van der Knaap MS;Recessive H-ABC Research Group
确定TUBB 4A突变阴性的髓鞘形成不足伴基底节和小脑萎缩（H-ABC）患者的基因缺陷。我们进行了纯合性定位和全外显子组测序（WES）来检测致病变异。我们使用Taqman分析进行群体筛选。我们开发了一种荧光素酶报告基因构建体来研究启动子突变对表达的影响。来自不同国家的14个家庭的16名患者符合H-ABC的MRI标准，表现出相似的严重临床表型，包括发育不全和严重的癫痫性脑病。大多数患者具有已知的罗姆族背景。5例患者的单核苷酸多态性阵列分析确定了13号染色体上的一个大的重叠纯合子区域。2例患者的WES显示UFM 1启动子区域存在纯合缺失。桑格测序证实了所有16例患者的这种变异的纯合性。所有患者都有一个共同的单倍型，表明创始人效应。对来自不同欧洲罗姆人小组的1,000名对照进行的筛选显示，突变的总体携带率为3%-25%。转染试验表明，删除显着降低表达在特定的中枢神经系统细胞系。UFM 1编码泛素折叠修饰因子1（UFM 1），其是参与蛋白质翻译后修饰的泛素样家族的成员。其确切的生物学作用尚不清楚。这项研究将UFM 1基因缺陷与疾病联系起来，并为UFM 1可能的功能网络提供了新的线索。
To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%–25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines. UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene defect with a disease and sheds new light on possible UFM1 functional networks.