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- Title
Somatic expansion behaviour ofthe (CTG)n repeat in myotonic dystrophy knock-in miceis differentially affected by Msh3 and Msh6 mismatch–repairproteins.
- Authors
vanden Broek, Walther J. A. A.; Nelen, Marcel R.; Wansink, DerickG.; Coerwinkel, MargaM.; teRiele, Hein; Groenen, PatriciaJ. T. A.; Wieringa, Bé
- Abstract
The mechanism of expansion of the (CTG)n repeatin myotonic dystrophy (DM1) patients and the cause of its pathobiologicaleffects are still largely unknown. Most likely, long repeats exerttoxicity at the level of nuclear RNA transport or splicing. Here,we analyse cis- and trans-actingparameters that determine repeat behaviour in novel mouse modelsfor DM1. Our mice carry ‘humanized’ myotonic dystrophyprotein kinase (Dmpk) allele(s) with either a (CTG)84 ora (CTG)11 repeat, inserted at the correct position intothe endogenous DM locus. Unlike in thehuman situation, the (CTG)84 repeat in the syntenic mouseenvironment was relatively stable during intergenerational segregation.However, somatic tissues showed substantial repeat expansions whichwere progressive upon aging and prominent in kidney, and in stomachand small intestine, where it was cell-type restricted. Other tissuesexamined showed only marginal size changes. The (CTG)11 allelewas completely stable, as anticipated. Introducing the (CTG)84 alleleinto an Msh3-deficient background completely blocked the somaticrepeat instability. In contrast, Msh6 deficiency resulted in a significant increasein the frequency of somatic expansions. Competition of Msh3 andMsh6 for binding to Msh2 in functional complexes with differentDNA mismatch-recognition specificity may explain why the somatic (CTG)n expansionrate is differentially affected by ablation of Msh3 and Msh6.
- Publication
Human Molecular Genetics, 2002, Vol 11, Issue 2, p191
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/11.2.191