Somatic Instability of the CTG Repeat in Mice Transgenic for the Myotonic Dystrophy Region is Age Dependent But Not Correlated to the Relative Intertissue Transcription Levels and Proliferative Capacities

A (CTG)n expansion in the 3′-untranslated region (UTR) of the DM protein kinase gene (DMPK) is responsible for causing myotonic dystrophy (DM). Major instability, with very large expansions between generations and high levels of somatic mosaicism, is observed in patients. There is a good correlation between repeat size (at least in leucocytes), clinical severity and age of onset. The trinucleotide repeat instability mechanisms involved in DM and other human genetic diseases are unknown. We studied somatic instability by measuring the CTG repeat length at several ages in various tissues of transgenic mice carrying a (CTG)55 expansion surrounded by 45 kb of the human DM region, using small-pool PCR. These mice have been shown to reproduce the intergenera-tional and somatic instability of the 55 CTG repeat suggesting that surrounding sequences and the chro-matin environment are involved in instability mechanisms. As observed in some of the tissues of DM patients, there is a tendency for repeat length and somatic mosai-cism to increase with the age of the mouse. Furthermore, we observed no correlation between the somatic mutation rate and tissue proliferation capacity. The somatic mutation rates in different tissues were also not correlated to the relative inter-tissue difference in transcrip-tional levels of the three genes (DMAHP, DMPK and 59) surrounding the repeat.