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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity
Fernando Morales,Jillian M. Couto,Catherine F. Higham,Grant Hogg,Patricia Cuenca,Claudia Braida,Richard H. Wilson,Berit Adam,Gerardo Del Valle,Roberto Brian,Mauricio Sittenfeld,Tetsuo Ashizawa,Alison Wilcox,Douglas E. Wilcox,Darren G. Monckton +14 more
TL;DR: Using single-molecule PCR, data establish a primary role for somatic instability in DM1 severity and show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers.
Journal ArticleDOI
Slipped (CTG)*(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair.
TL;DR: The fidelity of slipped-DNA repair is reported using human cell extracts and DNAs with slip-outs of (CAG)20 or (CTG)20 and a new form of error-prone repair was detected whereby excess repeats were incompletely excised, constituting a previously unknown path to generate expansions but not deletions.
Journal ArticleDOI
Somatic mosaicism in healthy human tissues.
TL;DR: The origins, prevalence and implications of somatic mosaicism in healthy human tissues are discussed and its implications for heightened disease risks are discussed.
Journal ArticleDOI
The contribution of cis-elements to disease-associated repeat instability: clinical and experimental evidence.
TL;DR: The available human data that supports the involvement of cis-elements in repeat instability with limited reference to model systems is reviewed, suggesting vastly different mechanisms may be responsible for repeat instability amongst the disease loci and between various tissues.
Journal ArticleDOI
Features of trinucleotide repeat instability in vivo
TL;DR: Most in vivo data are consistent with a model in which expansion and deletion occur by different mechanisms, and in mammals, microsatellite instability is complex and appears to be influenced by genetic, epigenetic and developmental factors.
References
More filters
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.