MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice

摘要: Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute ongoing disease progression through an affected individual's life with Huntington's or myotonic dystrophy. Broad ranges repeat instability arise between individuals expanded repeats, suggesting the existence modifiers instability. Mice show variable levels depending upon mouse strain. However, date genetic underlying these differences have not been identified. We that liver and striatum R6/1 (HD) (CAG)∼100 transgene, when present a congenic C57BL/6J (B6) background, incurred expansion-biased mutations, whereas was stable BALB/cByJ (CBy) background. Reciprocal mice revealed Msh3 gene as determinant for Expansion bias observed homozygous B6 on CBy while CAG tract stabilized congenics The stabilization dramatic deficiency Msh2. genes had identical promoters but differed coding regions showed strikingly different protein levels. MSH3 variant is highly expressed associated expansions, at barely detectable levels, associating stability. DHFR protein, which divergently transcribed from promoter shared by gene, did varied strains. Thus, naturally occurring polymorphisms instability, likely Since evidence supports modifier predictor disease, our data consistent hypothesis DNA repair may prognostic implications various repeat-associated diseases.