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.

Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability / D. Ronchi, A. Di Fonzo, W. Lin, A. Bordoni, C. Liu, E. Fassone, S. Pagliarani, M. Rizzuti, L. Zheng, M. Filosto, M.T. Ferrò, M. Ranieri, F. Magri, L. Peverelli, H. Li, Y. Yuan, S. Corti, M. Sciacco, M. Moggio, N. Bresolin, B. Shen, G.P. Comi. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 92:2(2013 Feb 07), pp. 293-300. [10.1016/j.ajhg.2012.12.014]

Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability

D. Ronchi
Primo
;
A. Bordoni;E. Fassone;S. Pagliarani;M. Ranieri;F. Magri;L. Peverelli;S. Corti;N. Bresolin;G.P. Comi
Ultimo
2013

Abstract

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.
enzymatic-properties; replication; disease; repair; deletions; protein; Twinkle; flap
Settore MED/26 - Neurologia
7-feb-2013
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0002929713000281-main.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 933.11 kB
Formato Adobe PDF
933.11 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/218970
Citazioni
  • ???jsp.display-item.citation.pmc??? 56
  • Scopus 107
  • ???jsp.display-item.citation.isi??? 96
social impact