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Myotonic dystrophy type 1 (DM1) is caused by an unstable expanded CTG repeat located within the  DMPK  gene 3’UTR. The nature, severity and age at onset of DM1 symptoms are very variable in patients. Different forms of the disease are described, among which the congenital form (CDM) is the most severe. Molecular mechanisms of DM1 are well characterized for the adult form and involve accumulation of mutant  DMPK  RNA forming foci in the nucleus. These RNA foci sequester proteins from the MBNL family and deregulate CELF proteins. These proteins are involved in many cellular mechanisms such as alternative splicing, transcriptional, translational and post-translational regulation miRNA regulation as well as mRNA polyadenylation and localization. All these mechanisms can be impaired in DM1 because of the deregulation of CELF and MBNL functions. The mechanisms involved in CDM are not clearly described. In order to get insight into the mechanisms underlying CDM, we investigated if expanded RNA nuclear foci, one of the molecular hallmarks of DM1, could be detected in human DM1 fetal tissues, as well as in embryonic and neonatal tissues from transgenic mice carrying the human  DMPK  gene with an expanded CTG repeat. We observed very abundant RNA foci formed by sense  DMPK  RNA and, to a lesser extent, antisense  DMPK  RNA foci. Sense  DMPK  RNA foci clearly co-localized with MBNL1 and MBNL2 proteins. In addition, we studied  DMPK  sense and antisense expression during development in the transgenic mice. We found that  DMPK  sense and antisense transcripts are expressed from embryonic and fetal stages in heart, muscle and brain and are regulated during development. These results suggest that mechanisms underlying DM1 and CDM involved common players including toxic expanded RNA forming numerous nuclear foci at early stages during development.

Sense and Antisense DMPK RNA Foci Accumulate in DM1 Tissues during Development