Myotonic Dystrophy type 1 (DM1) is a multi-system disorder characterised
by muscle wasting, myotonia, cardiac conduction defects, cataracts, and
neuropsychological dysfunction. DM1 is caused by expansion of a CTG repeat in the 3´
untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene.
A body of work demonstrates that DMPK mRNAs containing abnormally expanded
CUG repeats are toxic to several cell types. A core mechanism underlying symptoms of
DM1 is that mutant DMPK RNA interferes with the developmentally regulated
alternative splicing of defined pre-mRNAs by altering the function of important splicing
regulators such as MBNL1, CELF1 and hnRNP H. However, other RNA metabolism
pathways have also been found to be altered in DM1. Bidirectional transcription allows
generation of poly-CAG and poly-CUG mRNAs, both of which can generate toxic
polyaminoacidic proteins by Repeat Associated Non-ATG (RAN) translation. Double
stranded RNAs (CAG)•(CUG) and CUG expansion hairpins might act as Dicer
ribonuclease targets, thus leading to silencing of transcripts containing complementary
sequences. Upon transcription, mutant DMPK RNA coexists as ssCUG and dsCUG
forming hairpins. CELF1 accumulates in the nucleus and binds to ssCUG while
MBNL1 is sequestered in hairpins, thus altering their activity as splicing factors. ssCUG
also binds different types of nuclear factors such as transcription factors, contributing to
gene transcription deficiencies. More recently, several microRNAs have also been
found to be altered in DM1 affected muscles. In summary, mutant DMPK transcripts
have been shown to alter gene transcription, translation and alternative splicing of
specific gene transcripts, and have the ability to trigger gene-specific silencing effects
and microRNA dysregulation in DM1 cells. Therapies aimed at reversing these gene
expression alterations are likely to be effective ways to treat DM1.
Keywords: Muscleblind, myotonic dystrophy, missplicing, nucleotide
expansions, RNA toxicity.