Disruption of Splicing Regulated by a CUG-Binding Protein in Myotonic Dystrophy

Philips, Anne V.; Timchenko, Lubov; Cooper, Thomas A.

doi:10.1126/science.280.5364.737

Cited by 748 publications

(771 citation statements)

References 18 publications

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“…We suggest two possible explanations for a low FcRn affinity for IgG based on the current notion that patients with DM manifest a generalized defect in pre-mRNA processing [37][38][39]. Perhaps the FcRn α-chain itself is abnormally spliced in a subtle but critical fashion such that the IgG binding site is distorted while the albumin binding site is preserved.…”

Section: Pathophysiology Of Dm a Second Putatively Fcrn-related Diseasementioning

confidence: 93%

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Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

171

122

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The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.

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Section: Pathophysiology Of Dm a Second Putatively Fcrn-related Diseasementioning

confidence: 93%

“…DM is a genetic disease manifesting what appears to be a generalized defect in pre-mRNA processing [37][38][39]. Its phenotype is different from FHH.…”

Section: Pathophysiology Of Dm a Second Putatively Fcrn-related Diseasementioning

confidence: 99%

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

171

122

View full text Add to dashboard Cite

show abstract

“…[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%

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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“…12 In DM muscle, a downregulation of MBNL1 function and an upregulation of CELF1 function was shown. [15][16][17][18] For CELF1, multiple functions in RNA metabolism have been reported including regulation of alternative splicing, RNA stability and translational regulation of its RNA targets. [19][20][21] CELF1 interacts with the DMPK transcript, in particular with the (CUG) n repeat.…”

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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Disruption of Splicing Regulated by a CUG-Binding Protein in Myotonic Dystrophy

Cited by 748 publications

References 18 publications

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

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

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