Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy
Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy
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DOI：
10.1212/wnl.0000000000000716
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发表时间：
2014-08-19
期刊：
影响因子：
9.9
通讯作者：
Suomalainen, Anu
中科院分区：
文献类型：
--
作者：
Ahola, Sofia;Isohanni, Pirjo;Suomalainen, Anu
目的：报道芬兰高携带率线粒体翻译延长因子ts(EFTs)的新缺陷，并将该疾病组的表现从婴儿型心肌病扩展到青少年神经病/脑病。方法：DNA分析、全外显子组分析、蛋白质生物化学和蛋白质建模。结果：我们利用全外显子组测序在2个兄弟姐妹中发现了婴儿起病的线粒体心肌病、进展到幼年型Leigh综合征、神经病变和视神经萎缩的遗传原因。我们在编码线粒体EFTs的TSFM基因中发现了新的复合杂合突变c.944G>；A[p.C315Y]和c.856C>；T[p.Q286X]。同样的p.Q286X变异在来自第二个家系的患者中被发现为具有剪接点改变的复合杂合子，该患者患有幼年型视神经萎缩、周围神经病变和共济失调。我们的分子建模预测编码区突变会导致蛋白质不稳定，这在培养的患者细胞中得到了实验证实，存在线粒体翻译缺陷和缺乏EFT。以前在不同的人群中只有一种TSFM突变被描述，导致了一种伴随心肌病的婴儿致命的多系统疾病。来自35,000名芬兰人群对照的序列数据显示，在芬兰，P.Q286X突变的杂合携带者频率特别高，为1：80，但在该人群、我们的线粒体疾病患者集合或胎儿宫内死亡材料中未发现纯合子，表明纯合基因具有早期发育致死性。结论：除了早发性心肌病外，儿童和青少年脑病合并视神经和/或周围神经病变、共济失调或Leigh病时应考虑TSFM突变。
Objective: We report novel defects of mitochondrial translation elongation factor Ts (EFTs), with high carrier frequency in Finland and expand the manifestations of this disease group from infantile cardiomyopathy to juvenile neuropathy/encephalopathy disorders.Methods: DNA analysis, whole-exome analysis, protein biochemistry, and protein modeling.Results: We used whole-exome sequencing to find the genetic cause of infantile-onset mitochondrial cardiomyopathy, progressing to juvenile-onset Leigh syndrome, neuropathy, and optic atrophy in 2 siblings. We found novel compound heterozygous mutations, c.944G>A [p.C315Y] and c.856C>T [p.Q286X], in the TSFM gene encoding mitochondrial EFTs. The same p.Q286X variant was found as compound heterozygous with a splice site change in a patient from a second family, with juvenile-onset optic atrophy, peripheral neuropathy, and ataxia. Our molecular modeling predicted the coding-region mutations to cause protein instability, which was experimentally confirmed in cultured patient cells, with mitochondrial translation defect and lacking EFTs. Only a single TSFM mutation has been previously described in different populations, leading to an infantile fatal multisystem disorder with cardiomyopathy. Sequence data from 35,000 Finnish population controls indicated that the heterozygous carrier frequency of p.Q286X change was exceptionally high in Finland, 1: 80, but no homozygotes were found in the population, in our mitochondrial disease patient collection, or in an intrauterine fetal death material, suggesting early developmental lethality of the homozygotes.Conclusions: We show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease.