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Nucleic Acids Research, 2003, Vol. 31, No. 23 6733-6740
© 2003 Oxford University Press

Article

Mutagenic stress modulates the dynamics of CTG repeat instability associated with myotonic dystrophy type 1

Elisabeth Piñeiro, Laura Fernàndez-López, Josep Gamez1, Ricard Marcos, Jordi Surrallés and Antonia Velázquez*

Grup de Mutagènesi, Unitat de Genètica, Departament de Genètica i de Microbiologia, Edifici Cn, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona), Spain and 1 Departamento de Neurología, Hospital de la Vall d‘Hebron, Barcelona, Spain

*To whom correspondence should be addressed. Tel: +34 93 581 31 11; Fax: +34 93 581 23 87; Email: antonia.velazquez{at}uab.es
Correspondence may also be addressed to Jordi Surrallés. Email: jordi.surralles{at}uab.es
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

The molecular basis of the myotonic dystrophy type 1 is the expansion of a CTG repeat at the DMPK locus. The expanded disease-associated repeats are unstable in both somatic and germ lines, with a high tendency towards expansion. The rate of expansion is directly related to the size of the pathogenic allele, increasing the size heterogeneity with age. It has also been suggested that additional factors, including as yet unidentified environmental factors, might affect the instability of the expanded CTG repeats to account for the observed CTG size dynamics over time. To investigate the effect of environmental factors in the CTG repeat instability, three lymphoblastoid cell lines were established from two myotonic dystrophy patients and one healthy individual, and parallel cultures were concurrently expanded in the presence or absence of the mutagenic chemical mitomycin C for a total of 12 population doublings. The new alleles arising along the passages were analysed by radioactive small pool PCR and sequencing gels. An expansion bias of the stepwise mutation was observed in a (CTG)124 allele of a cell line harbouring two modal alleles of 28 and 124 CTG repeats. Interestingly, this expansion bias was clearly enhanced in the presence of mitomycin C. The effect of mitomycin C was also evident in the normal size alleles in two cell lines with alleles of 13/13 and 12/69 repeats, where treated cultures showed new longer alleles. In conclusion, our results indicate that mitomycin C modulates the dynamics of myotonic dystrophy-associated CTG repeats in LBCLs, enhancing the expansion bias of long-pathogenic repeats and promoting the expansion of normal length repeats.


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