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Dramatic, expansion-biased, age-dependent, tissue specific somatic mosaicism in a transgenic mouse model of triplet repeat instability

Fortune, M.T., Vassilopoulos, C., Coolbaugh, M.I., Siciliano, M.J., and Monckton, D.G. (2000) Dramatic, expansion-biased, age-dependent, tissue specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. Human Molecular Genetics, 9 (3). 439 -445. ISSN 0964-6906

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Publisher's URL: http://hmg.oupjournals.org/cgi/reprint/9/3/439.pdf

Abstract

Myotonic dystrophy type 1 (DM1) is one of a growing number of inherited human diseases whose molecular basis has been implicated as the expansion of a trinucleotide DNA repeat. Expanded disease-associated alleles of greater than 50 CTG repeats are unstable in both the germline and soma. Expansion of the unstable alleles over time and variation of the level of mutation between the somatic tissues of an individual are thought to account at least partially for the tissue specificity and progressive nature of the symptoms. We previously generated a number of transgenic mouse lines containing a large expanded CTG repeat tract that replicated a number of the features of unstable DNA in humans, including frequent sex-specific changes in allele length during intergenerational transmission. Small length change mutations were apparent in the somatic tissues of young mice in all of the lines generated, but the gross instability observed in human DM1 patients was not replicated. We now show that in one of the lines, Dmt -D, spectacular, expansion-biased, tissue-specific instability is observed in older mice. The highest levels of instability were detected in kidney with gains of greater than 500 repeats, representing a tripling of allele length, in some cells. Mosaicism accumulated in an age-dependent manner, but the tissue specificity did not obviously correlate with cell turnover. Such gross somatic mosaicism was not observed in three other lines examined, further emphasizing a role for flanking DNA in modulating repeat stability.

Item Type:Article
Status:Published
Refereed:Yes
Glasgow Author(s):Monckton, Prof Darren
Authors: Fortune, M.T., Vassilopoulos, C., Coolbaugh, M.I., Siciliano, M.J., and Monckton, D.G.
Subjects:R Medicine > RB Pathology
Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Human Molecular Genetics
ISSN:0964-6906

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