BACKGROUND The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. BODY: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. CONCLUSION The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted.

中文翻译：

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线粒体氨酰-tRNA 合成酶疾病：一组新兴的髓鞘形成发育障碍。


背景技术线粒体氨酰基-tRNA合成酶蛋白(mt-aaRS)是一组核编码酶，其促进20个氨基酸中的每一个与其同源tRNA分子缀合。线粒体疾病是一大类临床异质性疾病，具有不同的病因、发病年龄和所涉及的器官系统。与 mt-aaRS 突变相关的疾病与影响中枢神经系统并产生高度特征性 MRI 模式的特定综合征相关，典型的是 DARS2、EARS 和 AARS2 脑白质营养不良，它们是由线粒体天冬氨酰-tRNA 合成酶、线粒体谷氨酸 tRNA 突变引起的分别是丙氨酰-tRNA合成酶和线粒体丙氨酰-tRNA合成酶。身体：这些脑白质营养不良的疾病模式在发病年龄、疾病进展的性质以及所涉及的白质束的优势方面是不同的。在 DARS2 和 EARS2 疾病中，较早的疾病发作通常与更严重的大脑异常、快速的神经功能衰退和更大的残疾相关。迄今为止报道的AARS2脑白质营养不良病例中，所涉及的大脑区域几乎总是会进展为严重残疾和萎缩，通常在十年内发生。尽管大多数突变是以常染色体隐性方式遗传的复合杂合子，但在每种疾病中都发现了纯合子变异，并表现出较高的表型变异性。受影响的兄弟姐妹表现出广泛的疾病。结论 这些疾病中白质束的综合征性质和选择性脆弱性表明，线粒体功能障碍可能存在共同的机制作为研究目标。 有证据表明，每种 mt-aaRS 脑白质营养不良的临床变异性和白质束特异性取决于突变对线粒体翻译过程的典型和非典型影响。此外，根据细胞类型观察到对 mt-aaRS 突变的不同敏感性。大多数突变导致 mt-aaRS 酶功能至少部分保留，并对线粒体呼吸链复合物产生不同的影响。在 EARS2 和 AARS2 细胞中，这似乎会导致呼吸累积受损。 Mt-aaRS突变还可能影响其他生化途径，例如综合应激反应，这是真核细胞中的一种稳态程序，通常具有细胞保护作用，但当响应病理状态而异常激活时，可能导致细胞死亡。有必要对这组疾病进行系统评价，并进一步探索疾病模型和神经细胞中的疾病机制。