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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.

Original publication




Journal article


Nat Genet

Publication Date





223 - 231


Amino Acid Sequence, Cell Compartmentation, Chromosomes, Human, Pair 10, DNA Helicases, DNA Primase, DNA, Mitochondrial, Female, Finland, Genetic Linkage, Heterozygote, Humans, Italy, Male, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Ophthalmoplegia, Chronic Progressive External, Pakistan, Pedigree, Protein Conformation, Protein Transport, Sequence Deletion, Sequence Homology, Amino Acid