Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles.

Abstract

Nuclear speckles are storage sites for small nuclear RNPs (snRNPs) and other splicing factors. Current ideas about the role of speckles suggest that some pre-mRNAs are processed at the speckle periphery before being exported as mRNA. In myotonic dystrophy type 1 (DM1), the export of mutant DMPK mRNA is prevented by the presence of expanded CUG repeats that accumulate in nuclear foci. We now show that these foci accumulate at the periphery of nuclear speckles. In myotonic dystrophy type 2 (DM2), mRNA from the mutant ZNF9 gene is exported normally because the expanded CCUG repeats are removed during splicing. We now show that the nuclear foci formed by DM2 intronic repeats are widely dispersed in the nucleoplasm and not associated with either nuclear speckles or exosomes. We hypothesize that the expanded CUG repeats in DMPK mRNA are blocking a stage in its export pathway that would normally occur at the speckle periphery. Localization of the expanded repeats at the speckle periphery is not essential for their pathogenic effects because DM1 and DM2 are quite similar clinically.

• Authors: Ian Holt, Saloni Mittal, Denis Furling, Gillian S Butler-Browne, J David Brook, Glenn E Morris
• Journal: Genes to cells : devoted to molecular & cellular mechanisms (Genes Cells) Vol. 12 Issue 9 Pg. 1035-48 (Sep 2007) ISSN: 1356-9597 [Print] England
• PMID: 17825047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• CNBP protein, human
• DMPK protein, human
• Heterogeneous-Nuclear Ribonucleoproteins
• MBNL1 protein, human
• Nerve Tissue Proteins
• RNA Splicing Factors
• RNA, Messenger
• RNA-Binding Proteins
• Ribonucleoproteins, Small Nuclear
• YTHDC1 protein, human
• Myotonin-Protein Kinase
• Protein Serine-Threonine Kinases

Topics

• Antibodies (immunology)
• Cell Nucleus (metabolism)
• Cell Nucleus Structures (metabolism)
• Fetus (metabolism)
• HeLa Cells
• Heterogeneous-Nuclear Ribonucleoproteins (metabolism)
• Humans
• In Situ Hybridization
• Introns
• Models, Biological
• Mutation
• Myotonic Dystrophy (classification, genetics, metabolism)
• Myotonin-Protein Kinase
• Nerve Tissue Proteins (metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Splicing (physiology)
• RNA Splicing Factors
• RNA, Messenger (metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Ribonucleoproteins, Small Nuclear (metabolism)
• Trinucleotide Repeats