Résumé :
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INTRODUCTION : Myotonic dystrophy type I (DM1) is a dominant disease, showing highly variable multisystemic symptoms. The adult onset form may present muscle weakness, myotonia, cardio-respiratory problems, cataracts, hypersomnia, hyperinsulinism, behavioral and cognitive dysfunction An expansion of an unstable CTG repeat in the 3'UTR of the DMPK gene causes DM1. The normal DMPK gene contains 5-37 CTGs, while DM1 patients have repeats longer than 50 to more than 1000 CTGs. The CTG repeat tends to expand in subsequent generations and is correlated with the severity of the disease. Animal models revealed that the repeat expansion affects not only the expression of DMPK, but also the neighboring SIX5 gene and other gene products. Abnormal retention of mutant DMPK transcripts in nuclear foci alters the metabolism of other RNAs by disturbing the function of CUG-binding proteins involved in splicing or transcription regulation. In DM1 patients, several splicing defects have been identified in various tissues. AIM : To model DM1, we developed transgenic mice carrying the DM1 locus with 45 kb of human DNA sequence and different CTG repeat length. We characterized in detail the molecular and physiological features of these mice. METHOD : Mice carrying >300 CTG repeats showed very high levels of repeat instability biased towards expansion. After successive generations, we obtained transgenic mice carrying >1000 CTGs up to 1800 CTGs (DMSXL). We studied gene expression by qRT PCR, splicing abnormalities by PCR, nuclear accumulation of DMPK transcripts by FISH and measured strength with grip test. RESULTS : Expression of the human DMPK gene in DMSXL mice shows a similar profile to the endogenous Dmpk gene. DMSXL mice express sense but also antisense DMPK RNA. Expression levels vary between muscles. Abundant DMPK RNA foci and only mild splicing defects are observed in mice. Longer CTG repeats cause a more severe phenotype . CONCLUSION : DMSXL mice are a good model to study this pathology. Different molecular and physiological parameters can be used as readouts in preclinical therapeutic experiments.
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