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

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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Figure 1: Clinical findings and haplotype analysis.
Figure 2: Physical map of 14q23–q32 and molecular analyses of TDP1.
Figure 3: Crystal structure of TDP1 and its active site5.
Figure 4: Model of the resolution of stalled covalent topoisomerase I–DNA complexes that result in single-strand DNA breaks.

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Protein Data Bank

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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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Correspondence to James 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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