DNA2 mutation causing multisystemic disorder with impaired mitochondrial DNA maintenance

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.

N6-methyladenosine-modified circ_0000337 sustains bortezomib resistance in multiple myeloma by regulating DNA repair

“…The DNA replication helicase/nuclease 2 (DNA2) gene encodes a member of the helicase family (Wang et al, 2021). The encoded protein is a conserved helicase/nuclease involved in maintaining the stability of mitochondrial and nuclear DNA (Sun et al, 2022a). It was found that overexpressed DNA2 promotes tumor cell survival by overcoming replication stress on DNA replication forks induced by chemotherapy or radiotherapy (Kumar et al, 2017;Han et al, 2021).…”

Maintenance of genome integrity by the late-acting cytoplasmic iron-sulfur assembly (CIA) complex

“…However, a wide array of literature suggests that Fe-S biogenesis plays a role in numerous diseases which may result from the dysregulated global metabolic issues that arise from disrupted Fe-S containing enzymes such as those described in this review. For example, mutations associated with the [4Fe-4S] containing helicases have been implicated in the onset of disease as XPD mutations present as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy ( Taylor et al, 1997 ); FANCJ as Fancomi Anemia ( London et al, 2008 ); DDX11 as Warsaw Breakage Syndrome ( van der Lelij et al, 2010 ; van Schie JJMFaramarz et al, 2020 ); DNA2 as mitochondrial DNA depletion syndrome ( Sun et al, 2022 ); and RTEL mutations have been associated with familial pulmonary fibrosis ( Kannengiesser et al, 2015 ). Additionally, a majority of these enzymes are associated with cancer development including XPD, FANCJ, DDX11, RTEL, MUTYH, and NTHL1 ( Benhamou and Sarasin, 2002 ; Nicolo et al, 2008 ; Lubbe et al, 2009 ; Cantor and Guillemette, 2011 ; Mazzei et al, 2013 ; Weren et al, 2015 ; Yan et al, 2016 ; Das et al, 2020 ; Hutchcraft et al, 2021 ; Magrin et al, 2021 ; Mahtab et al, 2021 ).…”