Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy.
DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3'-UTR (3'-untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.
Mastroyiannopoulos
Nikolas P
NP
Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, PO Box 23462, 1683 Nicosia, Cyprus.
Shammas
Christos
C
Phylactou
Leonidas A
LA
D020413:3' Untranslated Regions; D000328:Adult; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009223:Myotonic Dystrophy / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D023121:RNA, Messenger, Stored / Q000235:genetics* / Q000378:metabolism; D015138:RNA, Nuclear / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
D020413:3' Untranslated Regions; C585517:DMPK protein, human; D012333:RNA, Messenger; D023121:RNA, Messenger, Stored; D015138:RNA, Nuclear; D016601:RNA-Binding Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases