Dataset Information

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington's disease.

ABSTRACT: Antagonist pleiotropy, where a gene exerts a beneficial effect at early stages and a deleterious effect later on in an animal's life, may explain the evolutionary persistence of devastating genetic diseases such as Huntington's disease (HD). To date, however, there is little direct experimental evidence to support this theory. Here, we studied a transgenic mouse carrying the HD mutation with a repeat of 50 CAGs (R6/2_50) that is within the pathological range of repeats causing adult-onset disease in humans. R6/2_50 mice develop characteristic HD brain aggregate pathology, with aggregates appearing predominantly in the striatum and cortex. However, they show few signs of disease in their lifetime. On the contrary, R6/2_50 mice appear to benefit from carrying the mutation. They have extended lifespans compared to wildtype (WT) mice, and male mice show enhanced fecundity. Furthermore, R6/2_50 mice outperform WT mice on the rotarod and show equal or better performance in the two choice discrimination task than WT mice. This novel mouse line provides direct experimental evidence that, although the HD mutation causes a fatal neurodegenerative disorder, there may be premorbid benefits of carrying the mutation.

SUBMITTER: Morton AJ

PROVIDER: S-EPMC6328633 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington's disease.

Morton A J AJ Skillings E A EA Wood N I NI Zheng Z Z

Scientific reports 20190110 1

Antagonist pleiotropy, where a gene exerts a beneficial effect at early stages and a deleterious effect later on in an animal's life, may explain the evolutionary persistence of devastating genetic diseases such as Huntington's disease (HD). To date, however, there is little direct experimental evidence to support this theory. Here, we studied a transgenic mouse carrying the HD mutation with a repeat of 50 CAGs (R6/2_50) that is within the pathological range of repeats causing adult-onset diseas ...[more]

PMID: 30631090

Similar Datasets

Project description:Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)?100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases.

Dataset Information

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington's disease.

Publications

Antagonistic pleiotropy in mice carrying a CAG repeat expansion in the range causing Huntington's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets