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Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia

BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) trans...

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Autores principales: Anjomani Virmouni, Sara, Sandi, Chiranjeevi, Al-Mahdawi, Sahar, Pook, Mark A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157886/
https://www.ncbi.nlm.nih.gov/pubmed/25198290
http://dx.doi.org/10.1371/journal.pone.0107416
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author Anjomani Virmouni, Sara
Sandi, Chiranjeevi
Al-Mahdawi, Sahar
Pook, Mark A.
author_facet Anjomani Virmouni, Sara
Sandi, Chiranjeevi
Al-Mahdawi, Sahar
Pook, Mark A.
author_sort Anjomani Virmouni, Sara
collection PubMed
description BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats). METHODOLOGY/PRINCIPAL FINDINGS: We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R. CONCLUSIONS/SIGNIFICANCE: Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.
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spelling pubmed-41578862014-09-09 Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia Anjomani Virmouni, Sara Sandi, Chiranjeevi Al-Mahdawi, Sahar Pook, Mark A. PLoS One Research Article BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats). METHODOLOGY/PRINCIPAL FINDINGS: We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R. CONCLUSIONS/SIGNIFICANCE: Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy. Public Library of Science 2014-09-08 /pmc/articles/PMC4157886/ /pubmed/25198290 http://dx.doi.org/10.1371/journal.pone.0107416 Text en © 2014 Anjomani Virmouni et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Anjomani Virmouni, Sara
Sandi, Chiranjeevi
Al-Mahdawi, Sahar
Pook, Mark A.
Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title_full Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title_fullStr Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title_full_unstemmed Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title_short Cellular, Molecular and Functional Characterisation of YAC Transgenic Mouse Models of Friedreich Ataxia
title_sort cellular, molecular and functional characterisation of yac transgenic mouse models of friedreich ataxia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157886/
https://www.ncbi.nlm.nih.gov/pubmed/25198290
http://dx.doi.org/10.1371/journal.pone.0107416
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