Pms2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion

Gomes-Pereira, M., Fortune, M.T., Ingram, L., McAbney, J.P. and Monckton, D.G. (2004) Pms2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Human Molecular Genetics, 13(16), 1815 -1825. (doi: 10.1093/hmg/ddh186)

Abstract

The expansion of CAG{middle dot}CTG repeat sequences is the cause of several inherited human disorders. Longer alleles are associated with an earlier age of onset and more severe symptoms, and are highly unstable in the germline and soma with a marked tendency towards repeat length gains. Germinal expansions underlie anticipation; whereas age-dependent, tissue-specific, expansion-biased somatic instability probably contributes toward the progressive nature and tissue-specificity of the symptoms. The mechanism(s) of repeat instability is not known, but recent data have implicated mismatch repair (MMR) gene mutS homologues in driving expansion. To gain further insight into the expansion mechanism, we have determined the levels of somatic mosaicism of a transgenic expanded CAG{middle dot}CTG repeat in mice deficient for the Pms2 MMR gene. Pms2 is a MutL homologue that plays a critical role in the downstream processing of DNA mismatches. The rate of somatic expansion was reduced by [~]50% in Pms2-null mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between Pms2+/+ and Pms2+/- mice, indicating that a single functional Pms2 allele is sufficient to generate normal levels of somatic mosaicism. These findings reveal that as well as MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex also play a central role in the accumulation of repeat length changes. These data suggest that somatic expansion results not by replication slippage, single stranded annealing or simple MutS-mediated stabilisation of secondary structures, but by inappropriate DNA mismatch repair.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McAbney, Mr John and Monckton, Professor Darren
• Authors: Gomes-Pereira, M., Fortune, M.T., Ingram, L., McAbney, J.P., and Monckton, D.G.
• Subjects: R Medicine > RB Pathology; Q Science > QH Natural history > QH426 Genetics
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Human Molecular Genetics
• ISSN: 0964-6906