Chapter 9

Expanded CTG Repeat Induced Molecular Alterations in Myotonic Dystrophy

Beatriz Llamusí, Ariadna Bargiela and Ruben Artero


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.

Total Pages: 221-245 (25)

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