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The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients
  1. Annalisa Botta (abottait{at}yahoo.it)
  1. Tor Vergata University of Rome, Italy
    1. Fabrizio Rinaldi (rinaldi.fabrizio{at}gmail.com)
    1. Tor Vergata University of Rome, Italy
      1. Claudio Catalli (claudio.catalli{at}gmail.com)
      1. Tor Vergata Hospital, Italy
        1. Lodovica Vergani (lodovica.vergani{at}unipd.it)
        1. University of Padoa, Italy
          1. Emanuela Bonifazi (emanuelabonifazi{at}yahoo.it)
          1. Tor Vergata Hospital, Italy
            1. Vincenzo Romeo (vincenzo.romeo{at}unipd.it)
            1. University of Padoa, Italy
              1. Emanuele Loro (emanuele.loro{at}unipd.it)
              1. University of Padoa, Italy
                1. Antonella Viola (antonellaviola{at}libero.it)
                1. Tor Vergata University of Rome, Italy
                  1. Corrado Angelini (corrado.angelini{at}unipd.it)
                  1. University of Padoa, Italy
                    1. Giuseppe Novelli (novelli{at}med.uniroma2.it)
                    1. Tor Vergata University of Rome, Italy

                      Abstract

                      Background: Myotonic dystrophy type 1 is caused by an unstable (CTG)n repetition located in the 3'UTR of the DM protein kinase gene (DMPK). Untranslated expanded DMPK transcripts are retained in ribonuclear foci which sequester CUG-binding proteins essential for the maturation of pre-mRNAs.

                      Aim: To investigate the effects of CTG expansion length on three molecular parameters associated with the DM1 muscle pathology: 1) the expression level of the DMPK gene; 2) the degree of splicing misregulation and 3) the number of ribonuclear foci.

                      Methods: Splicing analysis of the IR, MBNL1, c-TNT and CLCN1 genes, RNA-FISH experiments and determination of the DMPK expression on muscle samples from DM1 patients with an expansion below 500 repetitions (n=6), DM1 patients carrying a mutation above 1000 CTGs (n=6) and from controls (n=6). Results: The level of aberrant splicing of the IR, MBNL1, c-TNT and CLCN1 genes is different between the two groups of DM1 muscle samples and correlates with the CTG repeat length. RNA-FISH analysis revealed that the number of ribonuclear foci in DM1 muscle sections increases in patients with a higher (CTG)n number. No relationships were found between the expression level of the DMPK gene transcript and average expansion sizes.

                      Conclusion: The CTG repeat length plays a key role in the extent of splicing misregulation and foci formation, thus providing a useful link between the genotype and the molecular cellular phenotype in DM1.

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