Human Molecular Genetics, 2001, Vol. 10, No. 8 855-863
© 2001 Oxford University Press
‘Mitotic drive’ of expanded CTG repeats in myotonic dystrophy type 1 (DM1)
1Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA, 2Veterans Affairs Medical Center, Houston, TX 77030, USA, 3Department of Bioimmunotherapy and 4Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
In myotonic dystrophy type 1 (DM1), an expanded CTG repeat shows repeat size instability in somatic and germ line tissues with a strong bias toward further expansion. To investigate the mechanism of this expansion bias, 29 DM1 and six normal lymphoblastoid cell lines (LBCLs) were single-cell cloned from blood cells of 18 DM1 patients and six normal subjects. In all 29 cell lines, the expanded CTG repeat alleles gradually shifted toward further expansion by ‘step-wise’ mutations. Of these 29 cell lines, eight yielded a rapidly proliferating mutant with a gain of large repeat size that became the major allele population, eventually replacing the progenitor allele population. By mixing cell lines with different repeat expansions, we found that cells with larger CTG repeat expansion had a growth advantage over those with smaller expansions in culture. This growth advantage was attributable to increased cell proliferation mediated by Erk1,2 activation, which is negatively regulated by p21WAF1. This phenomenon, which we designated ‘mitotic drive’, is a novel mechanism which can explain the expansion bias of DM1 CTG repeat instability at the tissue level, on a basis independent of the DNA-based expansion models. The lifespans of the DM1 LBCLs were significantly shorter than normal cell lines. Thus, we propose a hypothesis that DM1 LBCLs drive themselves to extinction through a process related to increased proliferation.
+ To whom correspondence should be addressed at: Department of Neurology, SM1801, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Tel: +1 713 798 3953; Fax: +1 713 798 3128; Email: tetsuoa@bcm.tmc.edu
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