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

Takashima, Hiroshi; Boerkoel, Cornelius F.; John, Joy; Saifi, Gulam Mustafa; Salih, Mustafa A.M.; Armstrong, Dawna; Mao, Yuxin; Quiocho, Florante A.; Roa, Benjamin B.; Nakagawa, Masanori; Stockton, David W.; Lupski, James R.

doi:10.1038/ng987

Cited by 522Genetic Neurodegenerative DiseasesDNA Repair MechanismsHereditary Neurological Disorders

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

Takashima, Hiroshi, Boerkoel, Cornelius F., John, Joy, Saifi, Gulam Mustafa, Salih, Mustafa A.M., Armstrong, Dawna, Mao, Yuxin, Quiocho, Florante A. +4 more·2002·Nature Genetics

DOI 10.1038/ng987

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Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs covalently bound topoisomerase I-DNA complexes and is essential for preventing the formation of double-strand breaks that result when stalled topoisomerase I complexes interfere with DNA replication in yeast. 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 enzyme. 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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SCAN1 is caused by defective TDP1 and is characterized by peripheral neuropathy.
“SCAN1, caused by defective TDP1, is a similar neurodegenerative syndrome additionally characterized by peripheral neuropathy”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Takashima et al, 2002

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Authors: Takashima, H., Boerkoel, C. F., John, J., Saifi, G. M., Salih, M. A. M., Armstrong, D., Mao, Y., Quiocho, F. A., Roa, B. B., Nakagawa, M., Stockton, D. W., & Lupski, J. R.
Affiliations: Baylor College of Medicine (US)
Texas Children's Hospital (US)
Howard Hughes Medical Institute (US)
Kagoshima University (JP)
Corresponding author: Lupski, James R.
ORCID: Takashima, Hiroshi
Boerkoel, Cornelius F.
John, Joy
Salih, Mustafa A.M.
Mao, Yuxin
Lupski, James R.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2002-09-16
Volume: 32
Issue: 2
Pages: 267-272
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng987
OpenAlex: W2131418908
Cited by: 522
References: 29
Citations by year: 2026: 8 · 2025: 12 · 2024: 21 · 2023: 18 · 2022: 18 · 2021: 18 · 2020: 28 · 2019: 30 · 2018: 19 · 2017: 18 · 2016: 26 · 2015: 29 · 2014: 25 · 2013: 24 · 2012: 32
FWCI: 5.93
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords: TDP1, DNA repair, loss-of-function mutations, active site, postmitotic neurons, neuronal apoptosis, autosomal recessive inheritance, Saudi Arabian families, linkage mapping, protein structure modeling
MeSH terms: Adult, Binding Sites, Cerebellum, Chromosome Mapping, Chromosomes, Human, Pair 14, DNA Repair, Female, Humans, Male, Middle Aged, Pedigree, Phosphoric Diester Hydrolases, Sural Nerve, Protein Structure, Tertiary, Crystallography, X-Ray, Spinocerebellar Ataxias

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

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