Published online 1 December 2004
Nucleic Acids Research, Vol. 32 No. 21 © Oxford University Press 2004; all rights reserved
Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients
Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Sciences Center, 2121 West Holcombe Boulevard, Houston, TX 77030-3303, USA 1 Department of Neurology, Baylor College of Medicine, One Baylor Place, and VAMC, Houston, TX 77030, USA and 2 Department of Neurology, The University of Texas Medical Branch, 301 University Boulevard JSA9.128, Galveston, TX 77555-053, USA
* To whom correspondence should be addressed. Tel: +1 713 677 7664; Fax: +1 713 677 7689; Email: Rsinden{at}ibt.tamushsc.edu
Present addresses: Vera I. Hashem and Merhdad Khajavi, Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Kuniko Tsuji, Department of Neurology, Osaka Medical College, Takatsuki 568-8686, Japan
Received August 22, 2004; Revised November 6, 2004; Accepted November 14, 2004
Myotonic dystrophy type 1 (DM1) is caused by the expansion of a (CTG)·(CAG) repeat in the DMPK gene on chromosome 19q13.3. At least 17 neurological diseases have similar genetic mutations, the expansion of DNA repeats. In most of these disorders, the disease severity is related to the length of the repeat expansion, and in DM1 the expanded repeat undergoes further elongation in somatic and germline tissues. At present, in this class of diseases, no therapeutic approach exists to prevent or slow the repeat expansion and thereby reduce disease severity or delay disease onset. We present initial results testing the hypothesis that repeat deletion may be mediated by various chemotherapeutic agents. Three lymphoblast cell lines derived from two DM1 patients treated with either ethylmethanesulfonate (EMS), mitomycin C, mitoxantrone or doxorubicin, at therapeutic concentrations, accumulated deletions following treatment. Treatment with EMS frequently prevented the repeat expansion observed during growth in culture. A significant reduction of CTG repeat length by 100–350 (CTG)·(CAG) repeats often occurred in the cell population following treatment with these drugs. Potential mechanisms of drug-induced deletion are presented.
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