Department of Medical Genetics, Provincial Medical Genetics Program, Child and Family Research Institute, Children's and Women's Health Centre of British Columbia, University of British Columbia Vancouver, British Columbia, Canada.
Adv Exp Med Biol. 2010;685:75-83. doi: 10.1007/978-1-4419-6448-9_7.
Spinocerebellar ataxia with axonal neuropathy (SCAN 1) is an autosomal recessive disorder caused by a specific point mutation (c.1478A>G, p.H493R) in the tyrosyl-DNA phosphodiesterase (TDP1) gene. Functional and genetic studies suggest that this mutation, which disrupts the active site of the Tdp1 enzyme, causes disease by a combination of decreased catalytic activity and stabilization of the normally transient covalent Tdp1-DNA intermediate. This covalent reaction intermediate can form during the repair of stalled topoisomerase I-DNA adducts or oxidatively damaged bases at the 3' end of the DNA at a strand break. However, our current understanding of the biology of Tdp1 function in humans is limited and does not allow us to fully elucidate the disease mechanism.
脊髓小脑共济失调伴轴索性神经病（SCAN1）是一种常染色体隐性遗传病，由酪氨酰-DNA 磷酸二酯酶（TDP1）基因的特定点突变（c.1478A>G，p.H493R）引起。功能和遗传研究表明，这种突变破坏了 Tdp1 酶的活性位点，通过降低催化活性和稳定正常瞬态 Tdp1-DNA 中间产物的组合导致疾病。这种共价反应中间物可以在拓扑异构酶 I-DNA 加合物或 DNA 链断裂处 3' 末端氧化损伤碱基的修复过程中形成。然而，我们目前对 Tdp1 在人类中的功能生物学的理解是有限的，无法完全阐明疾病机制。
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