The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.

中文翻译：

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杂合子SSBP1开始丢失突变与听力损失和一个大型多代家族中的m.1555A> G mtDNA变体共分离。

m.1555A> G mtDNA变异导致母体遗传性耳聋，但临床外表变化很大的原因尚不清楚。外显子组测序鉴定出SSBP1中的一个杂合的起始丢失突变，编码单链结合蛋白1（SSBP1），在传输m.1555A> G的多代家庭中与听力损失隔离，与mtDNA耗尽和骨骼肌多处缺失有关。SSBP1突变降低稳态SSBP1水平，导致mtDNA代谢紊乱，可能以组织特异性方式加重了由于m.1555A> G引起的线粒体内翻译缺陷。该家族证明了罕见的反式遗传核修饰剂在mtDNA疾病的临床表达中的重要性。