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 pro tein kinase gene (DMPK) is responsible for causing myotonic dystrophy (DM), Major instability, with very large expansions between generation s and high levels of somatic mosaicism, is observed in patients, There is a good correlation between repeat size (at least in leucocytes), c linical severity and age of onset, The trinucleotide repeat instabilit y mechanisms involved in DM and other human genetic diseases are unkno wn, 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 intergeneration al and somatic instability of the 55 CTG repeat suggesting that surrou nding sequences and the chromatin environment are involved in instabil ity mechanisms. As observed in some of the tissues of DM patients, the re is a tendency for repeat length and somatic mosaicism to increase w ith the age of the mouse. Furthermore, we observed no correlation betw een the somatic mutation rate and tissue proliferation capacity. The s omatic mutation rates in different tissues were also not correlated to the relative inter-tissue difference in transcriptional levels of the three genes (DMAHP, DMPK and 59) surrounding the repeat.