The MT‐TL1 gene codes for the mitochondrial leucine transfer RNA (tRNA^Leu(UUR)) necessary for mitochondrial translation. Pathogenic variants in the MT‐TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT‐TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNA^Leu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient‐derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

中文翻译：

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线粒体基因组变异 m.3250T>C 作为线粒体心肌病的可能危险因素

MT-TL1基因编码线粒体翻译所需的线粒体亮氨酸转移 RNA (tRNA Leu ^(UUR) )。MT-TL1基因的致病变异导致人类线粒体病。MT-TL1基因中的 m.3250T>C 变体以前与运动不耐受和线粒体肌病有关，但该变体的疾病分类尚未得到一致报道。分子研究表明 m.3250T>C 变体不会改变 tRNA ^Leu(UUR)结构，但可能对氨酰化能力有适度的影响。然而，功能研究是有限的。我们的研究旨在进一步确定 m.3250T>C 变异的临床表现、遗传模式和分子病理学。从辛辛那提儿童医院医疗中心的线粒体疾病诊所和 GeneDx 实验室数据库中招募了具有 m.3250T>C 变体的家庭。受影响的个体最常出现心脏表现、运动不耐受和肌肉无力。肥厚型心肌病是最常见的心脏发现。许多无症状个体具有同质或接近同质水平的 m.3250T>C 变体，表明外显率不完整。患者来源的成纤维细胞表现出降低的 ATP 产生和增加的活性氧水平。