Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.

<h4>Background</h4>Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a pot...

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Autores principales:	Jong-Min Lee, Ricardo Mouro Pinto, Tammy Gillis, Jason C St Claire, Vanessa C Wheeler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/46ff4df3823c4acc941be4d6f92d8094
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spelling	oai:doaj.org-article:46ff4df3823c4acc941be4d6f92d80942021-11-18T06:47:07ZQuantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.1932-620310.1371/journal.pone.0023647https://doaj.org/article/46ff4df3823c4acc941be4d6f92d80942011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21897851/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.<h4>Methodology/principal findings</h4>To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.<h4>Conclusions/significance</h4>Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process.Jong-Min LeeRicardo Mouro PintoTammy GillisJason C St ClaireVanessa C WheelerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e23647 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jong-Min Lee Ricardo Mouro Pinto Tammy Gillis Jason C St Claire Vanessa C Wheeler Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
description	<h4>Background</h4>Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability.<h4>Methodology/principal findings</h4>To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type.<h4>Conclusions/significance</h4>Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process.
format	article
author	Jong-Min Lee Ricardo Mouro Pinto Tammy Gillis Jason C St Claire Vanessa C Wheeler
author_facet	Jong-Min Lee Ricardo Mouro Pinto Tammy Gillis Jason C St Claire Vanessa C Wheeler
author_sort	Jong-Min Lee
title	Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
title_short	Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
title_full	Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
title_fullStr	Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
title_full_unstemmed	Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.
title_sort	quantification of age-dependent somatic cag repeat instability in hdh cag knock-in mice reveals different expansion dynamics in striatum and liver.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/46ff4df3823c4acc941be4d6f92d8094
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Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver.

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