Jiayu Sun1,2,3, Wenwen Su1, Jianwen Deng4, Yao Qin1, Zhaoxia Wang4, Yuhe Liu5,6. 1. Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China. 2. Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 3. Department of Otolaryngology, Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. 4. Department of Neurology, Peking University First Hospital, Beijing, China. 5. Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, China. liuyuhefeng@163.com. 6. Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. liuyuhefeng@163.com.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Žygimantė Tarnauskaitė; Louise S Bicknell; Joseph A Marsh; Jennie E Murray; David A Parry; Clare V Logan; Michael B Bober; Deepthi C de Silva; Angela L Duker; David Sillence; Carol Wise; Andrew P Jackson; Olga Murina; Martin A M Reijns Journal: Hum Mutat Date: 2019-06-23 Impact factor: 4.878