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
Citations
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The multifaceted mismatch-repair system
TL;DR: This article reviews the current understanding of this multifaceted DNA-repair system in human cells and investigates how MMR status affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes.
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Mechanisms and functions of DNA mismatch repair
TL;DR: Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
Journal ArticleDOI
Expandable DNA repeats and human disease
TL;DR: It is becoming clear that the peculiar structures of repeat-containing transcripts are at the heart of the pathogenesis of these diseases, and the presence of expanded DNA repeats alters gene expression in human cells, leading to disease.
Journal ArticleDOI
Repeat instability: mechanisms of dynamic mutations
TL;DR: Experimental advances towards explaining the mechanisms of repeat instability have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
References
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Journal ArticleDOI
Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease
Russell G. Snell,J C MacMillan,Jeremy Peter Cheadle,I. Fenton,L. P. Lazarou,Peter Davies,Marcy E. MacDonald,James F. Gusella,Peter S. Harper,D.J. Shaw +9 more
TL;DR: The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene reveals a range of 30–70 repeats in affected individuals and 9–34 in normals, which suggests that normal gene function varies because of the size of the repeat in the normal range and a sex–specific modifying effect.
Journal ArticleDOI
hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6
Samir Acharya,Teresa Wilson,Scott Gradia,Michael F. Kane,Shawn Guerrette,Gerald T. Marsischky,Richard D. Kolodner,Richard Fishel +7 more
TL;DR: Analysis of the mismatched nucleotide-binding specificity of the hMSH2-hMSH3 and hMSh2-HMSH6 protein complexes showed that they have overlapping but not identical binding specificity, which helps to explain the distribution of mutations in different mismatch-repair genes seen in hereditary nonpolyposis colon cancer.
Journal ArticleDOI
Glutamine repeats and neurodegenerative diseases: molecular aspects
TL;DR: Eight severe inherited neurodegenerative diseases are caused by expansion of glutamine repeats in the affected proteins, whereas proteins with repeats of more than 40 glutamine residues precipitate as insoluble fibres, apparently because of a structural transition associated with the increased length.
Journal ArticleDOI
Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm.
H Telenius,B. Kremer,Y P Goldberg,J Theilmann,S E Andrew,J Zeisler,Shelin Adam,C Greenberg,Elizabeth Ives,Lorne A. Clarke +9 more
TL;DR: In this article, the authors analysed the CAG expansion in different tissues from 12 affected individuals and found that all tissues examined were found to display some repeat mosaicism, with the greatest levels detected in brain and sperm.
Journal ArticleDOI
Length-Dependent Gametic CAG Repeat Instability in the Huntington's Disease Knock-in Mouse
Vanessa C. Wheeler,Wojtek Auerbach,Jacqueline K. White,Jayalakshmi Srinidhi,Anna Auerbach,Angela Ryan,Mabel P. Duyao,Vladimir Vrbanac,Meredith Weaver,James F. Gusella,Alexandra L. Joyner,Marcy E. MacDonald +11 more
TL;DR: The results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers.