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Spinocerebellar ataxia with axonal neuropathy(SCAN1) Hiroshi TAKASHIMA 1 , Kimiyoshi ARIMURA 1 1Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Keyword: 劣性遺伝性脊髄小脳変性症 , DNA修復 , SSBR pp.379-386
Published Date 2006/6/10
DOI https://doi.org/10.11477/mf.1431100146
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Hereditary ataxia with neuropathy is clinically and genetically heterogeneous. To identify one of the causes of hereditary ataxia, we investigated a Saudi Arabian family with ataxia and peripheral neuropathy and named this disease spinocerebellar ataxia with axonal neuropathy(SCAN1). Using the positional cloning method, we previously identified a mutation of Tyrosyl-DNA phosphodiesterase 1(TDP1)as a cause of SCAN1. TDP1 hydrolyzes 3'-phosphotyrosyl bonds to repair covalently bound topoisomerase I-DNA complexes. All patients with SCAN1 had a homozygous His493Arg mutation. Because His 493 is located in the active site of the enzyme, we thought that loss-of-function of TDP1 induces the disease. However, a recent report revealed that His493Arg causes a special functional mutation which causes the accumulation of intermediates in the TDP1-DNA covalent reaction whose half-life is definitely longer than those of the wild type and other mutations. Since topoisomeraseⅠ always works during the transcription process, the presence of intermediates should affect the transcription process. Because abnormal transcriptions lead to neuronal degeneration in polyglutamine diseases, TDP1-DNA intermediates or loss-of-function TDP1 could lead to abnormal transcription in SCAN1 patients.


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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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