Document Detail

The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model.
MedLine Citation:
PMID:  17024371     Owner:  NLM     Status:  MEDLINE    
Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. Patients have progressive neurodegeneration of the dorsal root ganglia (DRG) and in later stages the cerebellum may be involved. The expanded GAA-TR sequence is unstable in somatic cells in vivo, and although the mechanism of instability remains unknown, we hypothesized that age-dependent and tissue-specific somatic instability may be a determinant of the progressive pathology involving DRG and cerebellum. We show that transgenic mice containing the expanded GAA-TR sequence (190 or 82 triplets) in the context of the human FXN locus show tissue-specific and age-dependent somatic instability that is compatible with this hypothesis. Small pool PCR analysis, which allows quantitative analysis of repeat instability by assaying individual transgenes in vivo, showed age-dependent expansions specifically in the cerebellum and DRG. The (GAA)(190) allele showed some instability by 2 months, progressed at about 0.3-0.4 triplets per week, resulting in a significant number of expansions by 12 months. Repeat length was found to determine the age of onset of somatic instability, and the rate and magnitude of mutation. Given the low level of cerebellar instability seen by others in multiple transgenic mice with expanded CAG/CTG repeats, our data indicate that somatic instability of the GAA-TR sequence is likely mediated by unique tissue-specific factors. This mouse model will serve as a useful tool to delineate the mechanism(s) of disease-specific somatic instability in FRDA.
Rhonda M Clark; Irene De Biase; Anna P Malykhina; Sahar Al-Mahdawi; Mark Pook; Sanjay I Bidichandani
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-09-21
Journal Detail:
Title:  Human genetics     Volume:  120     ISSN:  0340-6717     ISO Abbreviation:  Hum. Genet.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-20     Completed Date:  2007-04-16     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7613873     Medline TA:  Hum Genet     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  633-40     Citation Subset:  IM    
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MeSH Terms
Age Factors
Cerebellum / metabolism*
Disease Models, Animal
Friedreich Ataxia / genetics,  pathology
Ganglia, Spinal / metabolism*
Gene Frequency
Iron-Binding Proteins / genetics*
Mice, Transgenic
Trinucleotide Repeat Expansion / genetics*
Trinucleotide Repeats / genetics*
Grant Support
070235//Wellcome Trust; R01 NS047596/NS/NINDS NIH HHS; //Wellcome Trust
Reg. No./Substance:
0/Iron-Binding Proteins; 0/frataxin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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