title: HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence.
abstract: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder associated with a (CUG)n expansion in the 3'-untranslated region of the DMPK (DM1 protein kinase) gene. Mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus of DM1 cells and form discrete foci. The nuclear sequestration of RNA binding proteins and associated factors binding to the CUG expansions is believed to be responsible for several of the splicing defects observed in DM1 patients and could ultimately be linked to DM1 muscular pathogenesis. Several RNA binding proteins capable of co-localizing with the nuclear-retained mutant DMPK mRNAs have already been identified but none can account for the nuclear retention of the mutant transcripts. Here, we have employed a modified UV crosslinking assay to isolate proteins bound to mutant DMPK-derived RNA and have identified hnRNP H as an abundant candidate. The specific binding of hnRNP H requires not only a CUG repeat expansion but also a splicing branch point distal to the repeats. Suppression of hnRNP H expression by RNAi rescued nuclear retention of RNA with CUG repeat expansions. The identification of hnRNP H as a factor capable of binding and possibly modulating nuclear retention of mutant DMPK mRNA may prove to be an important link in our understanding of the molecular mechanisms that lead to DM1 pathogenesis.
authors: Department of Molecular Biology, Beckman Research Institute of the City of Hope Duarte, CA, USA.
authors: Dong-Ho
authors: DH
authors: Kim
authors: Marc-Andre
authors: MA
authors: Langlois
authors: Kwang-Back
authors: KB
authors: Lee
authors: Arthur D
authors: AD
authors: Riggs
authors: Jack
authors: J
authors: Puymirat
authors: John J
authors: JJ
authors: Rossi
mesh_terms: D020413:3' Untranslated Regions / Q000737:chemistry; D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D042622:DNA Repeat Expansion; D019281:Dimerization; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D020413:3' Untranslated Regions; C585517:DMPK protein, human; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D012333:RNA, Messenger; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases