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Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repe...

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Autores principales: Wheeler, Vanessa C., Dion, Vincent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990408/
https://www.ncbi.nlm.nih.gov/pubmed/33579861
http://dx.doi.org/10.3233/JHD-200426
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author Wheeler, Vanessa C.
Dion, Vincent
author_facet Wheeler, Vanessa C.
Dion, Vincent
author_sort Wheeler, Vanessa C.
collection PubMed
description At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.
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spelling pubmed-79904082021-04-14 Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models Wheeler, Vanessa C. Dion, Vincent J Huntingtons Dis Review At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction. IOS Press 2021-02-09 /pmc/articles/PMC7990408/ /pubmed/33579861 http://dx.doi.org/10.3233/JHD-200426 Text en © 2021 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review
Wheeler, Vanessa C.
Dion, Vincent
Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title_full Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title_fullStr Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title_full_unstemmed Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title_short Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models
title_sort modifiers of cag/ctg repeat instability: insights from mammalian models
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990408/
https://www.ncbi.nlm.nih.gov/pubmed/33579861
http://dx.doi.org/10.3233/JHD-200426
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