Identification of a (CUG)n Triplet Repeat RNA-Binding Protein and Its Expression in Myotonic Dystrophy

Timchenko, Lubov; Miller, Jill W.; Timchenko, Nikolaj A.; DeVore, Druery R.; Datar, Kshama V.; Li, Lin; Roberts, Robert; Caskey, C. Thomas; Swanson, Maurice S.

doi:10.1093/nar/24.22.4407

Cited by 423 publications

(407 citation statements)

References 43 publications

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“…[11][12][13] This deregulation of CUGBP1 results in delay of skeletal muscle differentiation and insulin resistance in DM1 disease. Since the expression of antisense RNA restored efficiency of muscle differentiation and glucose uptake (Figures 4 and 5, and Table 1), we next examined whether the antisense RNA brings CUGBP1 expression to the normal levels.…”

Section: Cugbp1 Levels In Infected Dm1 Cellsmentioning

confidence: 99%

“…[2][3][4] At the molecular levels, the DM1 phenotype is most likely caused by a complex molecular pathogenesis, including deficiency of myotonic dystrophy myotonin kinase (DMPK) protein, [5][6][7] haplo-insufficiency of a neighboring homeobox gene (particular the DM locus-associated homeodomain protein (DMAHP/Six 5 gene) 8 and the WD-repeat gene (DMWD) 9 and a trans-dominant misregulation of RNA homeostasis. [10][11][12][13][14][15][16] Recent experiments from transgenic mice, expressing an untranslated expanded CUG repeat under the control of the human skeletal actin promoter, showed that expanded CUG repeats are sufficient to generate DM1 muscle phenotype. 17 These data suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Furling

Doucet²,

Ma³

et al. 2003

Gene Ther

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Myotonic dystrophy (DM1) is caused by the expansion of a trinucleotide repeat (CTG) located in the 3 0 untranslated region of the myotonic dystrophy protein kinase gene, for which currently there is no effective treatment. The data available suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis. This indicates that the specific targeting of the mutant DMPK transcripts is essential to raise the rationale basis for the development of a specific gene therapy for DM1. We have produced a retrovirus which expresses a 149-bp antisense RNA complementary to the (CUG)13 repeats and to the 110-bp region following the repeats sequence to increase the specificity. This construct was introduced into human DM1 myoblasts, resulting in a preferential decrease in mutant DMPK transcripts, and effective restoration of human DM1 myoblast functions such as myoblast fusion and the uptake of glucose. It was previously shown that delay of muscle differentiation and insulin resistance in DM1 are associated with misregulation of CUGBP1 protein levels. The analysis of CUGBP1 levels and activity in DM1 cells expressing the antisense RNA indicated a correction of CUGBP1 expression in infected DM1 cells. We therefore show that current antisense RNA delivered in vitro using a retrovirus is not only capable of inhibiting mutant DMPK transcripts, but also can ameliorate dystrophic muscle pathology at the cellular levels. Gene Therapy (2003) 10, 795-802.

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Section: Cugbp1 Levels In Infected Dm1 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Furling

Doucet²,

Ma³

et al. 2003

Gene Ther

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“…The first protein that prompted researchers to look for the mechanism of aberrant splicing in DM1 was the CUGBP1 (Timchenko et al, 1996a(Timchenko et al, , 1996bPhilips et al, 1998). CUGBP1 is up-regulated in DM1 due to PKC (protein kinase C) pathway activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization (KuyumcuMartinez et al, 2007).…”

Section: Nuclear Rna Retentionmentioning

confidence: 99%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus 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.

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“…[19][20][21] CELF1 interacts with the DMPK transcript, in particular with the (CUG) n repeat. 14 In a mouse model overexpressing CELF1, several typical histological and mis-splicing features of DM were demonstrated. 22 The second candidate, MBNL1, is known to bind to the expanded CUG repeat and to colocalize with the nuclear RNA foci, causing a local reduction and therefore loss of function of MBNL1 protein because of sequestration and binding to the repeat tract in the nuclear foci.…”

Section: Introductionmentioning

confidence: 99%

“…Two proteins that bind to repeat-expanded RNA are CELF1 (CUGBP, Elav-like family member 1) 14 and MBNL1 (muscleblind-like splicing regulator 1). 12 In DM muscle, a downregulation of MBNL1 function and an upregulation of CELF1 function was shown.…”

Section: Introductionmentioning

confidence: 99%

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

et al. 2016

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The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

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Identification of a (CUG)n Triplet Repeat RNA-Binding Protein and Its Expression in Myotonic Dystrophy

Cited by 423 publications

References 43 publications

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

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