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首页> 外文期刊>American journal of medical genetics, Part A >Refining the phenotype of the THG1L THG1L (p.Val55Ala mutation)‐related mitochondrial autosomal recessive congenital cerebellar ataxia
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Refining the phenotype of the THG1L THG1L (p.Val55Ala mutation)‐related mitochondrial autosomal recessive congenital cerebellar ataxia

机译：精制THG1L THG1L的表型（P.VAL55ALA突变） - 相关线粒体常染色体隐性先天性小脑共济失调

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Abstract Roughly 40 genes have been linked to autosomal recessive (AR) ataxia syndromes. Of these, at least 10 encode gene products localizing to the mitochondrion. tRNA‐histidine guanylyltransferase 1 like ( THG1L ) localizes to the mitochondrion and catalyzes the 3′–5′ addition of guanine to the 5′‐end of tRNA‐histidine. Previously, three siblings with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy on brain magnetic resonance imaging (MRI) were reported to carry homozygous V55A mutations in THG1L . Fibroblasts derived from these individuals showed abnormal mitochondrial networks when subjected to obligatory oxidative phosphorylation. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes were found in Exac or gnomAD. This variant is reported with an allelic frequency of 0.02% in Exac, and is not listed in gnomAD. A similar phenotype was recently reported for another, homozygous variant p.L294P was reported with a similar, but more severely affected phenotype [Shaheen et al. (2019); Genetics in Medicine 21: 545–552]. Here, we report two additional Ashkenazi Jewish patients, carrying the same homozygous V55A mutation. We present bioinformatic analyses of the V55A mutation demonstrating high conservation in metazoan species. We refine the clinical and radiological phenotype and discuss the uniqueness of the clinical course of this novel mitochondrial AR ataxia in comparison to the diverse molecular etiologies and clinical phenotypes of other known mitochondrial AR ataxias.
机译：摘要大约40个基因已与常染色体隐性（AR）共济失调综合征有关。其中，至少10个编码基因产物定位于线粒体。 TRNA-组氨酸冠状阴三晶酶1（THG1L）定位于线粒体，并将3'-5'添加到TRNA组氨酸的5'末端。以前，据报道，据报道，脑磁共振成像（MRI）上具有早期发病性功能障碍，发育延迟，金字塔瘤和小脑萎缩的三个兄弟姐妹在THG1L中携带纯合V55A突变。衍生自这些个体的成纤维细胞在经受强制氧化磷酸化时显示出不同的线粒体网络。载流量为0.8％，但没有THG1L v55a纯合子，在3,232个无关的阿基妥妥妥斯犹太人的队列中发现，并且在exac或gnomad中没有发现纯合子。该变体报告，EXAC的等位基因频率为0.02％，并未列入GNOMAD。最近报道了一种类似的表型，纯合变体P.L294P呈纯合变体P.L294P，其具有类似但更严重的表型[Shaheen等人。 （2019）;医学遗传学21：545-552。在这里，我们报告了另外两名阿什妥妥犹太患者，携带相同的纯合V55A突变。我们呈现V55A突变的生物信息分析，证明了甲烷物种的高保守。我们优化临床和放射性表型，并与其他已知的线粒体ATAXIAS的不同分子病因和临床表型相比，探讨了这种新型线粒体AR共济失调的临床进程的独特性。

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