FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance
FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance
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DOI：
10.1016/j.ymgme.2018.07.014
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发表时间：
2018-11-01
影响因子：
3.8
通讯作者：
Wong, Lee-Jun C.
中科院分区：
文献类型：
--
作者：
Almannai, Mohammed;Wang, Julia;Wong, Lee-Jun C.
越来越多的线粒体疾病被发现是由核编码线粒体氨酰-tRNA 合成酶的致病性变异引起的。 FARS2 编码线粒体苯丙氨酰-tRNA 合成酶 (mtPheRS)，该酶将苯丙氨酸转移至线粒体中的同源 tRNA。自 2012 年报告第一例病例以来，迄今已报告共有 21 名患有 FARS2 缺陷的受试者，其疾病严重程度介于两种表型之间；早发性癫痫性脑病和以痉挛性截瘫为特征的不太严重的表型。在本报告中，我们介绍了来自 12 个家族的另外 15 名个体，他们大多是致病性变异 Y144C 纯合子的阿拉伯人，该变异与更严重的早发表型相关。迄今为止，已知的独特致病性 FARS2 变异总数为 21 种，其中包括在 4 个个体中报告的 3 种不同的部分基因缺失。除了大的缺失之外，除了两个（一个氨基酸的框内缺失和一个剪接位点变体）之外的所有变体都是错义的。所有大的缺失和单剪接位点变体都在带有错义变体的Mans中。这表明功能完全丧失可能与生命不相容。在本报告中，我们还回顾了此处报道的选定 FARS2 致病变异的结构、功能和进化意义。
An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in Mans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.