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The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients
  1. A Botta1,
  2. F Rinaldi1,
  3. C Catalli2,
  4. L Vergani3,
  5. E Bonifazi2,
  6. V Romeo3,
  7. E Loro3,
  8. A Viola1,
  9. C Angelini3,
  10. G Novelli1,2
  1. 1
    Department of Biopathology, Tor Vergata University of Rome, Rome, Italy
  2. 2
    Tor Vergata Hospital, Medical Genetics Section, Rome, Italy
  3. 3
    Department of Neurosciences, University of Padova, Padoa, Italy
  1. Dr A Botta, Tor Vergata University of Rome, Department of Biopathology, Via Montpellier, 1, 00133 Rome, Italy; abottait{at}


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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  • Funding: Study supported by PRIN grant #2005064759, Telethon grant #GPP07250 and AFM grant #13360. Muscle samples were provided by Telethon Biobank N° GTB07001.

  • Competing interests: None.

  • Patient consent: Obtained.