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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The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair.
J M M van Oers,Y Edwards,Richard Chahwan,Weijia Zhang,Cameron Smith,Ximo Pechuan,Sonja Schaetzlein,Bo Jin,Yarong Wang,Aviv Bergman,Matthew D. Scharff,Winfried Edelmann +11 more
TL;DR: It is shown that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR, and it is demonstrated that MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.
Journal ArticleDOI
Chromatin regulation of DNA damage repair and genome integrity in the central nervous system.
TL;DR: In this paper, a review of the sources and types of DNA damage and the relevant repair pathways in the nervous system is presented, and the authors discuss the chromatin regulation of these processes and summarize the contribution of genomic instability to neurodegenerative diseases.
Journal ArticleDOI
Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders.
Karen Usdin,Bruce E. Hayward,Daman Kumari,Rachel Adihe Lokanga,Nicholas Sciascia,Xiao-Nan Zhao +5 more
TL;DR: This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility.
Journal ArticleDOI
The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington's Disease: A Historical Perspective.
TL;DR: The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington's disease (HD), opened up a new era of human genetics and provided explanations for some old problems as discussed by the authors.
Journal ArticleDOI
Maternal germline-specific effect of DNA ligase I on CTG/CAG instability
Stéphanie Tomé,Gagan B. Panigrahi,Arturo López Castel,Laurent Foiry,David W. Melton,Geneviève Gourdon,Christopher E. Pearson +6 more
TL;DR: Unlike other DNA metabolizing enzymes studied to date, LigI has a highly specific role in CTG repeat maintenance in the maternal germline, involved in mediating CTG expansions and in the avoidance of maternal CTG contractions.
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.