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Article
Nature Genetics  28, 223 - 231 (2001)
doi:10.1038/90058

Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria

Johannes N. Spelbrink1, 16, Fang-Yuan Li2, 16, Valeria Tiranti3, Kaisu Nikali4, Qiu-Ping Yuan2, Muhammed Tariq5, Sjoerd Wanrooij1, Nuria Garrido1, Giacomo Comi6, Lucia Morandi7, Lucio Santoro8, Antonio Toscano9, Gian-Maria Fabrizi10, Hannu Somer11, Rebecca Croxen12, David Beeson12, Joanna Poulton13, Anu Suomalainen4, 14, Howard T Jacobs1, 15, Massimo Zeviani3 & Catharina Larsson2

1  Institute of Medical Technology & Tampere University Hospital, Tampere, Finland.

2  Department of Molecular Medicine, Karolinska Hospital, CMM L8:01, S-171 76 Stockholm, Sweden.

3  Division of Biochemistry & Genetics, National Neurological Institute "C. Besta", Milan, Italy.

4  National Public Health Institute, Department of Human Molecular Genetics, Helsinki, Finland.

5  Department of Neurology, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.

6  Dino Ferrari Center, Institute of Clinical Neurology, University of Milan School of Medicine, Milan, Italy.

7  Division of Neuromuscular Disorders, National Neurological Institute "C. Besta", Milan, Italy.

8  Department of Neurological Sciences, University of Naples "Federico II", Naples, Italy.

9  Institute of Clinical Neurology, University of Messina, Messina, Italy.

10  Institute of Clinical Neurology, University of Verona, Verona, Italy.

11  Department of Neurology, University of Helsinki, Helsinki, Finland.

12  Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, U.K.

13  University of Oxford Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DS, U.K.

14  Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

15  Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, U.K.

16  These authors contributed equally to this work.

Correspondence should be addressed to Johannes N. Spelbrink hans.spelbrink@uta.fi
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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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