Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders.

中文翻译：

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mtDNA维持基因SSBP1的显着突变导致视神经萎缩和中央凹病

编码线粒体DNA（mtDNA）复制机制成分的基因中的突变会导致mtDNA耗竭综合征（MDS），该综合征将眼功能与严重的神经系统综合征相关联。在这里，我们确定了单链结合蛋白1（SSBP1杂合错义突变）在5个无关的家族中，导致线粒体单链DNA结合蛋白中的R38Q和R107Q氨基酸发生变化，这是与mtDNA复制有关的关键蛋白。所有受影响的个体均出现视神经萎缩，并伴有中央凹病。为了揭示潜在的SSBP1突变的结构特征，我们确定了修改后的SSBP1晶体结构。结构分析表明，这两种突变都影响二聚体相互作用，并可能扭曲了DNA结合区。使用患者的成纤维细胞，我们验证了R38Q变体使SSBP1二聚体/四聚体形成不稳定，影响mtDNA复制，并诱导mtDNA消耗。我们的研究表明SSBP1中的突变 引起一种常见的中央凹病并伴有中央凹病的视神经萎缩形式，带来了对mtDNA维持障碍的见解。