Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability

Dario Ronchi, Alessio Di Fonzo, Weiqiang Lin, Andreina Bordoni, Changwei Liu, Elisa Fassone, Serena Pagliarani, Mafalda Rizzuti, Li Zheng, Massimiliano Filosto, Maria Teresa Ferrò, Michela Ranieri, Francesca Magri, Lorenzo Peverelli, Hongzhi Li, Yate Ching Yuan, Stefania Corti, Monica Sciacco, Maurizio Moggio, Nereo BresolinBinghui Shen, Giacomo Pietro Comi

Research output: Contribution to journalArticlepeer-review


Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.

Original languageEnglish
Pages (from-to)293-300
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Feb 7 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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