Dataset Information

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

ABSTRACT:

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.

SUBMITTER: Anjomani Virmouni S

PROVIDER: S-EPMC4157886 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

Anjomani Virmouni Sara S Sandi Chiranjeevi C Al-Mahdawi Sahar S Pook Mark A MA

PloS one 20140908 9

<h4>Background</h4>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).<h4>Methodology/principal findings</h4>We now report ex ...[more]

PMID: 25198290

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Project description:BackgroundFriedreich ataxia is an autosomal recessive hereditary spinocerebellar disorder, characterized by progressive limb and gait ataxia due to proprioceptive loss, often complicated by cardiomyopathy, diabetes and skeletal deformities. Friedreich ataxia is the most common hereditary ataxia, with a reported prevalence of 1:20 000 - 1:50 000 in Central Europe. Previous reports from south Norway have found a prevalence varying from 1:100 000 - 1:1 350 000; no studies are previously done in the rest of the country.MethodsIn this cross-sectional study, Friedreich ataxia patients were identified through colleagues in neurological, pediatric and genetic departments, hospital archives searches, patients' associations, and National Centre for Rare Disorders. All included patients, carriers and controls were investigated clinically and molecularly with genotype characterization including size determination of GAA repeat expansions and frataxin measurements. 1376 healthy blood donors were tested for GAA repeat expansion for carrier frequency analysis.ResultsTwenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752-1:112]) was found. Homozygous GAA repeat expansions in the FXN gene were found in 27/29, while two patients were compound heterozygous with c.467 T < C, L157P and the deletion (g.120032_122808del) including exon 5a. Two additional patients were heterozygous for GAA repeat expansions only. Significant differences in the level of frataxin were found between the included patients (N = 27), carriers (N = 37) and controls (N = 27).ConclusionsIn this first thorough study of a complete national cohort of Friedreich ataxia patients, and first nation-wide study of Friedreich ataxia in Norway, the prevalence of Friedreich ataxia in Norway is lower than in Central Europe, but higher than in the last Norwegian report, and as expected from migration studies. A south-north prevalence gradient is present. Based on Hardy Weinberg's equilibrium, the carrier frequency of 1:196 is consistent with the observed prevalence. All genotypes, and typical and atypical phenotypes were present in the Norwegian population. The patients were phenotypically similar to European cohorts. Frataxin was useful in the diagnostic work-up of heterozygous symptomatic cases.

Project description:BACKGROUND: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. METHODOLOGY/PRINCIPAL FINDINGS: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. CONCLUSIONS/SIGNIFICANCE: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.

Dataset Information

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

Background

Methodology/principal findings

Conclusions/significance

Publications

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

Similar Datasets

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