Abstract
The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.
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Acknowledgements
Financial support was provided by the Academy of Finland, Tampere University Hospital Medical Research Fund, Juselius Foundation, Finnish Cultural Foundation, Swedish Medical Research Council, Torsten and Ragnar Söderberg Memory Foundations, Telethon grant 1180, “Ricerca Finalizzata” grant ICS030.3/RF98.37, a Pier Franco and Luisa Mariani Foundation grant to M.Z. and the EU BIOMED2 programme. R.C. and D.B. were supported by the Medical Research Council (U.K.) and the Muscular Dystrophy Campaign/Myasthenia Gravis Association. J.P. is a Royal Society University Research Fellow. We thank Anja Rovio for technical assistance, Leena Peltonen for sharing her expertise, Sanna Lehtinen for expression studies of Twinkle-EGFP in A549-derived cells and Dale Wigley and Ian Holt for many useful discussions.
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Spelbrink, J., Li, FY., Tiranti, V. et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28, 223–231 (2001). https://doi.org/10.1038/90058
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DOI: https://doi.org/10.1038/90058
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