Résumé :
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Myotonic dystrophy type I (DM1) is a dominant disease, highly variable and associated with multisystemic symptoms. The adult onset form presents muscle weakness, myotonia, cardio-respiratory problems, cataracts, hypersomnia, hyperinsulinism, testicular atrophy and early frontal balding in males. Behavioral changes and cognitive dysfunction are also frequent. The more severe congenital form (CDM) is characterized at birth by general hypotonia, respiratory distress and difficulty in sucking and swallowing. The genetic mutation causing DM1 is the expansion of an unstable CTG repeat in the 3'UTR of a gene encoding a protein kinase (DMPK). The normal DMPK gene contains 5-37 CTG repeats, while DM1 patients have repeats expanding from 50 to several thousand CTG repeats. The size of the CTG repeat generally increases from generation to generation and is correlated with the severity of the disease. The development of animal models revealed that DM1 is not a simple dosage, or gain or loss-of-function disorder. The repeat expansion affects not only the expression of DMPK, but also the neighboring SIX5 gene, as well as others gene products: abnormal retention of mutant DMPK transcripts in cell nuclei in foci alters the metabolism of other RNA, by disturbing the function of CUG-binding proteins involved in splicing or transcription regulation. In DM1 patients, a growing number of splicing defects have been identified in various tissues.We have developed transgenic mice carrying the DM1 locus covering about 45 kb of human DNA sequence with different CTG repeat lengths. Mice carrying >300 CTG repeats showed very high levels of CTG repeat instability biased towards expansion. After successive generations, we obtained transgenic mice carrying >1000 CTG and up to 1800 CTG (named DMSXL mice). The human DMPK transgene is expressed under the control of its own promoter and shows a pattern of expression similar to that observed in humans and for the endogenous Dmpk gene. However, DMPK transgene expression levels remain low and only homozygous mice show a phenotype. DMSXL homozygous mice display abundant DMPK nuclear foci, MBNL1 sequestration and splicing abnormalities. They are currently used in several collaborative gene therapy experiments in muscle and using systemic approaches. The molecular and physiological characterisation of DMSXL mice in several tissues will be presented and discussed. This work received financial support from AFM, ANR and Inserm.
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