Mutation of TDP1, encoding a topoisomerase I–dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy (original) (raw)

Nature Genetics volume 32, pages 267–272 (2002)Cite this article

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I–DNA complexes1,2,3 and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast4. Here we show that a deficiency of this DNA repair pathway in humans does not predispose to neoplasia or dysfunctions in rapidly replicating tissues, but instead causes spinocerebellar ataxia with axonal neuropathy (SCAN1) by affecting large, terminally differentiated, non-dividing neuronal cells. Using genome-wide linkage mapping and a positional candidate approach in a Saudi Arabian family affected with autosomal recessive SCAN1, we identified a homozygous mutation in TDP1 (A1478G) that results in the substitution of histidine 493 with an arginine residue. The His493 residue is conserved in TDP1 across species and is located in the active site of the enzyme3,5. Protein modeling predicts that mutation of this amino acid to arginine will disrupt the symmetric structure of the active site. We propose that loss-of-function mutations in TDP1 may cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in postmitotic neurons.

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Acknowledgements

We thank the participating families for their cooperation, and S. Rosenberg, E.L. Zechiedrich and H. Zoghbi for critical review. H.T. and G.M.S. are recipients of postdoctoral fellowships from the Charcot–Marie–Tooth Association. This study was supported in part by grants from the National Institute of Diabetes, Digestive, and Kidney Diseases, US National Institutes of Health, to C.F.B.; from the Education, Science, Sports and Culture of Japan, the Nervous and Mental Disorders and Central Nervous System Degenerative Disorders divisions of the Ministry of Health and Welfare of Japan to M.N.; from the National Eye Institute, US National Institutes of Health, National Institutes of Health Mental Retardation Research Center, and Kleberg Foundation to D.W.S.; and from the National Institute of Neurological Disorders and Stroke, US National Institutes of Health, and the Muscular Dystrophy Association to J.R.L.

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Author notes

  1. Hiroshi Takashima and Cornelius F. Boerkoel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA
    Hiroshi Takashima, Cornelius F. Boerkoel, Joy John, Gulam Mustafa Saifi, Benjamin B. Roa, David W. Stockton & James R. Lupski
  2. Kleberg Genotyping Center, Baylor College of Medicine, Houston, Texas, USA
    Joy John & David W. Stockton
  3. Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, Riyadh, Saudi Arabia
    Mustafa A.M. Salih
  4. Department of Pathology, Texas Children's Hospital, Houston, Texas, USA
    Dawna Armstrong
  5. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA
    Yuxin Mao & Florante A. Quiocho
  6. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
    Florante A. Quiocho
  7. Baylor DNA Diagnostic Laboratory, Baylor College of Medicine, Houston, Texas, USA
    Benjamin B. Roa
  8. Third Department of Internal Medicine, Kagoshima University School of Medicine, Kagoshima, Japan
    Masanori Nakagawa
  9. Departments of Medicine and of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA
    David W. Stockton
  10. Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
    James R. Lupski

Authors

  1. Hiroshi Takashima
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  2. Cornelius F. Boerkoel
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  3. Joy John
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  4. Gulam Mustafa Saifi
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  5. Mustafa A.M. Salih
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  6. Dawna Armstrong
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  7. Yuxin Mao
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  8. Florante A. Quiocho
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  9. Benjamin B. Roa
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  10. Masanori Nakagawa
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  11. David W. Stockton
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  12. James R. Lupski
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Correspondence toJames R. Lupski.

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Takashima, H., Boerkoel, C., John, J. et al. Mutation of TDP1, encoding a topoisomerase I–dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.Nat Genet 32, 267–272 (2002). https://doi.org/10.1038/ng987

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