Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China.
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
J Hum Genet. 2022 Dec;67(12):691-699. doi: 10.1038/s10038-022-01075-4. Epub 2022 Sep 5.
To describe a novel DNA2 variant contributing to defects in mtDNA maintenance and mtDNA depletion syndrome (MDS), and the clinical and histological findings associated with this variation.
Herein, we describe the case of a patient who presented with hearing loss and myopathy, given the family history of similar findings in the father, was evaluated by sequencing of the deafness gene panel, mitochondrial genome, and the exome. Furthermore, tissue staining, mtDNA copy number detection, mtDNA sequencing, and long-range polymerase chain reaction tests were also conducted on the muscle biopsy specimen. In vitro experiments, including analyses of the mtDNA copy number; levels of ATP, ATPase, and reactive oxygen species (ROS); and the membrane potential, were performed.
The DNA2 heterozygous truncating variant c. 2368C > T (p.Q790X) was identified and verified as the cause of an mtDNA copy number decrement in both functional experiments and muscle tissue analyses. These changes were accompanied by reductions in ATP, ATPase, and ROS levels.
The DNA2 variant was a likely cause of MDS in this patient. These findings expand the mutational spectrum of MDS and improve our understanding of the functions of DNA2 by revealing its novel role in mtDNA maintenance.
描述一种导致线粒体 DNA 维持缺陷和线粒体 DNA 耗竭综合征（MDS）的新型 DNA2 变异，以及与该变异相关的临床和组织学发现。
在此，我们描述了一位患者的病例，该患者因听力损失和肌病就诊，鉴于其父亲有类似发现的家族史，我们对其进行了耳聋基因panel、线粒体基因组和外显子组测序。此外，还对肌肉活检标本进行了组织染色、mtDNA 拷贝数检测、mtDNA 测序和长距离聚合酶链反应检测。还进行了体外实验，包括 mtDNA 拷贝数分析；ATP、ATP 酶和活性氧（ROS）水平；以及膜电位分析。
鉴定并验证了 DNA2 杂合截断变异 c.2368C>T（p.Q790X）是导致该患者 mtDNA 拷贝数减少的原因，这些变化在功能实验和肌肉组织分析中均得到证实。这些变化伴随着 ATP、ATP 酶和 ROS 水平的降低。
该 DNA2 变异可能是该患者 MDS 的原因。这些发现扩展了 MDS 的突变谱，并通过揭示 DNA2 在 mtDNA 维持中的新作用，加深了我们对其功能的理解。
