Mutations in DNA2 Link Progressive Myopathy to Mitochondrial DNA Instability

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• 作者：Dario Ronchi¹ ; ¹⁰ ; Alessio Di Fonzo¹ ; ¹⁰ ; Weiqiang Lin² ; ¹⁰ ; Andreina Bordoni¹ ; Changwei Liu² ; Elisa Fassone³ ; Serena Pagliarani¹ ; Mafalda Rizzuti¹ ; Li Zheng² ; Massimiliano Filosto⁴ ; Maria Teresa Ferrò ; ⁵ ; Michela Ranieri¹ ; Francesca Magri¹ ; Lorenzo Peverelli⁷ ; Hongzhi Li⁸ ; Yate-Ching Yuan⁸ ; Stefania Corti¹ ; ⁶ ; Monica Sciacco⁷ ; Maurizio Moggio⁷ ; Nereo Bresolin¹ ; ⁶ ; ⁹ ; Binghui Shen² ; ^{bshen@coh.org} ; Giacomo Pietro Comi¹ ; ⁶ ; ^{giacomo.comi@unimi.it}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：7 February, 2013
• 年：2013
• 卷：92
• 期：2
• 页码：293-300
• 全文大小：883 K

文摘

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.