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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Erratum: Mechanisms of trinucleotide repeat instability during human development
TL;DR: In Table 1 in the above article, there was a mistake on the row starting with DM1 (myotonic dystrophy type 1), the 'Repeat number (disease)' column incorrectly stated 50.
Journal ArticleDOI
Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset
Meera Swami,Audrey E. Hendricks,Tammy Gillis,Tiffany Massood,Jayalakshmi S. Mysore,Richard H. Myers,Vanessa C. Wheeler +6 more
TL;DR: After accounting for constitutive repeat length, somatic instability was found to be a significant predictor of onset age, with larger repeat length gains associated with earlier disease onset, consistent with the hypothesis that somatic HD CAG repeat length expansions in target tissues contribute to the HD pathogenic process.
Journal ArticleDOI
DNA structures, repeat expansions and human hereditary disorders.
TL;DR: The replication model of repeat expansion as mentioned in this paper stipulates that unusual structures of expandable repeats stall replication fork progression, whereas extra repeats are added during replication fork restart, which could lead to their expansion.
Journal ArticleDOI
Huntington’s disease
TL;DR: This review is based on the experience of leading (SJT) and working in the multidisciplinary Huntington's disease clinic at the National Hospital for Neurology and Neurosurgery, supported by an up to date literature review performed using PubMed and a review of the Cochrane database.
Journal ArticleDOI
CAG Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing Haplogroup
Simon C. Warby,Alexandre Montpetit,Anna Hayden,Anna Hayden,Jeffrey B. Carroll,Stefanie L. Butland,Henk Visscher,Jennifer A. Collins,Alicia Semaka,Thomas J. Hudson,Thomas J. Hudson,Michael R. Hayden +11 more
TL;DR: The current data argue that cis-elements have a major predisposing influence on CAG instability in HTT and provide an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.
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.