Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy

Savkur, Rajesh S.; Philips, Anne V.; Cooper, Thomas A.

doi:10.1038/ng704

Cited by 711 publications

(790 citation statements)

References 39 publications

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“…In addition, it has been suggested that the insulin resistance that occurs in DM1 muscles may be the consequences of alteration in the splicing of insulin receptor pre-mRNA caused by the increased expression of CUG-binding proteins. 34 We showed that the defective action of insulin on glucose uptake retained in DM1 muscle cell cultures was also completely restored in (CUG) 13 antisense-infected DM1 myoblasts. Thus, decreased levels of mutant DMPK transcripts by the antisense inhibit the abnormal upregulation of the total levels of CUG-binding protein that may counteract the aberrant regulation of the insulin receptor and restore the action of insulin on glucose uptake in DM1 myoblasts.…”

Section: Targeting Of Mutant Dmpk Transcripts D Furling Et Almentioning

confidence: 82%

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: Targeting Of Mutant Dmpk Transcripts D Furling Et Almentioning

confidence: 82%

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Furling

Doucet²,

Ma³

et al. 2003

Gene Ther

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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%

“…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

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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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“…Mis-regulation by MBNL1 and CUGBP1 acts synergistically in the splicing misregulation of a wide group of developmentally regulated genes (Kanadia et al, 2003). These include the IR (insulin receptor gene; Savkur et al, 2001), c-TNT (cardiac troponin T gene; Philips et al, 1998), CLCN1 (muscle chloride channel 1 gene; Mankodi et al, 2002), and those encoding dystrophin (Nakamori et al, 2007) and microtubule-associated tau (Sergeant et al, 2001). Any alterations in the CLCN1, IR and c-TNT RNA splicing can cause myotonia, insulin resistance and cardiac defects respectively .…”

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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Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy

Cited by 711 publications

References 39 publications

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

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

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

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