Molecular Genetic Basis of Myotonic Dystrophy


Myotonic dystrophy (DM) comprises at least two genetically distinct forms, both of which are caused by expansions of microsatellite repeats. Expansion of a CTG repeat in the DMPK gene leads to DM1, whereas expansion of a CCTG repeat in the ZNF9 gene causes DM2. In both cases, the repeat units may expand to several thousand repeats. Strikingly similar phenotypes, mutation types and pathological findings suggest a common pathogenic mechanism for both DM1 and DM2. However, the differences between DM1 and DM2 may be a consequence of locus‐specific effects involving haploinsufficiency of different genes and downstream events triggered by CUG or CCUG transcripts. Altogether, the complex DM1 and DM2 phenotypes are probably caused by specific combinations of several possible pathogenic pathways in different tissues of individual patients.

Key Concepts:

  • Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are complex multisystemic disorders with highly similar but not identical symptoms.

  • Both DM1 and DM2 are caused by expansions of microsatellite repeats, however, in two distinct genes (DMPK and ZNF9).

  • Mechanisms leading to the DM1 and DM2 symptoms are very complex with several possible pathogenic pathways.

  • The best described pathogenic pathway involves the misregulation of two alternative splicing regulators, CUG‐BP1 (gain of function) and MBNL1 (loss of function), leading to target‐specific splicing alterations.

  • Both CUG‐BP1 and MBNL1 are multifunctional proteins; thus, their activation/sequestration have effect on further cellular functions such as transcription, translation and mRNA decay.

  • Both DM1 and DM2 causing expansions can also lead to decreased levels of proteins coded by genes around and near to the expansion sites, such as DMPK, ZNF9, SIX5 and DMWD.

  • The exact molecular pathogenic mechanism in certain tissues is probably not uniform, it rather represents a specific combination of several distinct pathogenic pathways.

Keywords: CUG‐BP1; DM1; DM2; DMPK; MBNL1; microsatellite expansions; myotonic dystrophy; RNA gain of function; ZNF9

Figure 1.

Schematic view of the possible pathogenic pathways of DM1 and DM2.



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Further Reading

Batra R, Charizanis K and Swanson MS (2010) Partners in crime: bidirectional transcription in unstable microsatellite disease. Human Molecular Genetics 19: R77–R82.

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Ranum LP and Day JW (2004) Myotonic dystrophy: RNA pathogenesis comes into focus. American Journal of Human Geneticss 74: 793–804.

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Radvanszky, Jan, and Kadasi, Ludevit(Jan 2013) Molecular Genetic Basis of Myotonic Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023864]