Human Molecular Genetics Advance Access published online on June 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh186
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Institute of Biomedical and Life Sciences, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, United Kingdom
* To whom correspondence should be addressed. E-mail: d.monckton{at}bio.gla.ac.uk.
The expansion of CAG·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·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
Article
Pms2 is a genetic enhancer of trinucleotide CAG·CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion
Abstract 
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. De Temmerman, S. Seneca, A. Van Steirteghem, P. Haentjens, J. Van der Elst, I. Liebaers, and K.D. Sermon CTG repeat instability in a human embryonic stem cell line carrying the myotonic dystrophy type 1 mutation Mol. Hum. Reprod., July 1, 2008; 14(7): 405 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Entezam and K. Usdin ATR protects the genome against CGG{middle dot}CCG-repeat expansion in Fragile X premutation mice Nucleic Acids Res., February 11, 2008; 36(3): 1050 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V C Wheeler, F Persichetti, S M McNeil, J S Mysore, S S Mysore, M E MacDonald, R H Myers, J F Gusella, N S Wexler, and The US Venezuela Collaborative Research Group Factors associated with HD CAG repeat instability in Huntington disease J. Med. Genet., November 1, 2007; 44(11): 695 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lin and J. H. Wilson Transcription-Induced CAG Repeat Contraction in Human Cells Is Mediated in Part by Transcription-Coupled Nucleotide Excision Repair Mol. Cell. Biol., September 1, 2007; 27(17): 6209 - 6217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lloret, E. Dragileva, A. Teed, J. Espinola, E. Fossale, T. Gillis, E. Lopez, R. H. Myers, M. E. MacDonald, and V. C. Wheeler Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice Hum. Mol. Genet., June 15, 2006; 15(12): 2015 - 2024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Pelletier, B. T. Farrell, J. J. Miret, and R. S. Lahue Mechanistic features of CAG*CTG repeat contractions in cultured cells revealed by a novel genetic assay Nucleic Acids Res., September 30, 2005; 33(17): 5667 - 5676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Nag, M. Fasullo, Z. Dong, and A. Tronnes Inverted repeat-stimulated sister-chromatid exchange events are RAD1-independent but reduced in a msh2 mutant Nucleic Acids Res., September 15, 2005; 33(16): 5243 - 5249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Wells, R. Dere, M. L. Hebert, M. Napierala, and L. S. Son Advances in mechanisms of genetic instability related to hereditary neurological diseases Nucleic Acids Res., July 8, 2005; 33(12): 3785 - 3798. [Abstract] [Full Text] [PDF]
|
|