Spinocerebellar ataxia with axonal neuropathy.
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.
Walton
Cheryl
C
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.
Interthal
Heidrun
H
Hirano
Ryuki
R
Salih
Mustafa A M
MA
Takashima
Hiroshi
H
Boerkoel
Cornelius F
CF
D025063:Chromosome Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D053960:DNA Breaks; D004260:DNA Repair / Q000235:genetics; D049914:DNA Repair-Deficiency Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D020754:Spinocerebellar Ataxias / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D004247:DNA; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human; D004264:DNA Topoisomerases, Type I