Journal ArticleDOI
Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.
Kevin Manley,Thomas L. Shirley,Thomas L. Shirley,Lorraine Flaherty,Lorraine Flaherty,Anne Messer,Anne Messer +6 more
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TLDR
The results show that Msh2 is required for somatic instability of the HD CAG repeat, suggesting important functional correlations between repeat length and pathology.Abstract:
Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.read more
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Journal ArticleDOI
The nucleotide sequence, DNA damage location, and protein stoichiometry influence the base excision repair outcome at CAG/CTG repeats.
Agathi-Vasiliki Goula,Christopher E. Pearson,Julie A. Della Maria,Yvon Trottier,Alan E. Tomkinson,David M. Wilson,Karine Merienne +6 more
TL;DR: The results show that the BER stoichiometry, nucleotide sequence, and DNA damage position modulate repair outcome and suggest that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability.
Journal ArticleDOI
Tissue specificity in DNA repair: lessons from trinucleotide repeat instability
TL;DR: A better understanding of this type of genome instability will provide a foundation for studying tissue-specific DNA repair more generally, which has implications in cancer and other diseases caused by mutations in the caretakers of the genome.
Journal ArticleDOI
Heterozygosity for a hypomorphic Polβ mutation reduces the expansion frequency in a mouse model of the Fragile X-related disorders.
TL;DR: It is shown here that heterozygosity for a Y265C mutation in Polβ, a key polymerase in the BER pathway, is enough to significantly reduce both the number of expansions seen in paternal gametes and the extent of somatic expansion in some tissues of the FXD mouse, suggesting that events in theBER pathway downstream of the generation of nicks are also important for repeat expansion.
Journal ArticleDOI
Selectable system for monitoring the instability of CTG/CAG triplet repeats in mammalian cells.
TL;DR: A selectable assay to detect contractions of CTG/CAG triplets is developed and the frequency of spontaneous contractions is determined and it is shown that treatments with DNA-damaging agents stimulate repeat contractions.
Journal ArticleDOI
Fen1 does not control somatic hypermutability of the (CTG) n · (CAG) n repeat in a knock-in mouse model for DM1
Walther J. A. A. van den Broek,Marcel R. Nelen,Godfried W. van der Heijden,Derick G. Wansink,Bé Wieringa +4 more
TL;DR: It is proposed that Fen1, despite its role in DNA repair and replication, is not primarily involved in maintaining stability at the DM1 locus, and the frequency of somatic DM1 (CTG) n · (CAG) n repeat instability was essentially unaltered in mice with Fen1 haploinsufficiency up to 1.5 years of age.
References
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Journal ArticleDOI
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
Marcy E. MacDonald,Christine Ambrose,Mabel P. Duyao,Richard H. Myers,Carol Lin,Lakshmi Srinidhi,Glenn Barnes,Sherryl A.M. Taylor,Marianne James,Nicolet Groot,Heather MacFarlane,Barbara Jenkins,Mary Anne Anderson,Nancy S. Wexler,James F. Gusella,Gillian P. Bates,Sarah Baxendale,Holger Hummerich,Susan F. Kirby,Mike North,S. Youngman,Richard Mott,Günther Zehetner,Zdenek Sedlacek,Annemarie Poustka,Anna-Maria Frischauf,Hans Lehrach,Alan Buckler,Deanna M. Church,Lynn Doucette-Stamm,Michael Conlon O'Donovan,Laura Riba-Ramirez,Manish A. Shah,Vincent P. Stanton,Scott A. Strobel,Karen M. Draths,Jennifer L. Wales,Peter B. Dervan,David E. Housman,Michael R. Altherr,Rita Shiang,Leslie M. Thompson,Thomas J. Fielder,John J. Wasmuth,Danilo A. Tagle,John Valdes,Lawrence W. Elmer,Marc W. Allard,Lucio H. Castilla,Manju Swaroop,Kris Blanchard,Francis S. Collins,Russell G. Snell,Tracey Holloway,Kathleen Gillespie,Nicole A. Datson,Duncan Shaw,Peter S. Harper +57 more
TL;DR: In this article, the authors used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect, which is expanded and unstable on HD chromosomes.
Journal Article
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group.
Manish A. Shah,Nicole A. Datson,Lakshmi Srinidhi,Vincent P. Stanton,Marcy E. MacDonald,Marc W. Allard,S. Youngman,Anna-Maria Frischauf,Richard Mott,KM Draths,Günther Zehetner,C. O’Donovan,Thomas J. Fielder,Bruce G. Jenkins,Manju Swaroop,Sherryl A.M. Taylor,Lynn Doucette-Stamm,Heather MacFarlane,Scott A. Strobel,H. E. McFarlane,Alan Buckler,Nicolet Groot,Holger Hummerich,Deanna M. Church,M. A. Anderson,Marianne James,Glenn Barnes,M. Christine,Francis S. Collins,Mabel P. Duyao,Peter B. Dervan,Gillian P. Bates,T Holloway,Peter S. Harper,TW Mcdonald,M North,K Blanchard,John J. Wasmuth,D. Shaw,Hans Lehrach,Danilo A. Tagle,Annemarie Poustka,David E. Housman,T. Huntington,Zdenek Sedlacek,Laura Riba,Susan F. Kirby,Carol Lin,Richard H. Myers,Leslie M. Thompson,Russell G. Snell,Michael Conlon O'Donovan,K Gillespie,Rita Shiang,Nancy S. Wexler,Christine Ambrose,J. F. Gusella,Sarah Baxendale,N. Groat,John Valdes +59 more
TL;DR: The Huntington's disease mutation involves an unstable DNA segment, similar to those described in fragile X syndrome, spino-bulbar muscular atrophy, and myotonic dystrophy, acting in the context of a novel 4p16.3 gene to produce a dominant phenotype.
Journal ArticleDOI
Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice
Laura Mangiarini,Kirupa Sathasivam,Mary J. Seller,Barbara A. Cozens,Alex Harper,Colin Hetherington,Martin Lawton,Yvon Trottier,Hans Lehrach,Stephen W. Davies,Gillian P. Bates +10 more
TL;DR: Mice have been generated that are transgenic for the 5' end of the human HD gene carrying CAG/polyglutamine repeat expansion that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures.
Journal ArticleDOI
Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer
TL;DR: Cells and mice that are deficient for the presumed DNA mismatch repair (MMR) gene Msh2 have lost mismatch binding and have acquired microsatellite instability, a mutator phenotype, and tolerance to methylating agents, suggesting that Msh1 is involved in safeguarding the genome from promiscuous recombination.
Journal ArticleDOI
Inactivation of the mouse Huntington's disease gene homolog Hdh.
Mabel P. Duyao,Anna Auerbach,Angela Ryan,Francesca Persichetti,Glenn Barnes,Sandra M. McNeil,P. Ge,Jean-Paul Vonsattel,James F. Gusella,Alexandra L. Joyner,Marcy E. MacDonald +10 more
TL;DR: That Hdh inactivation does not mimic adult HD neuropathology suggests that the human disease involves a gain of function, and that huntingtin is critical early in embryonic development, before the emergence of the nervous system.