Résumé :
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Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG)n repeat expansion in intron 1 of the ZNF9 gene. This causes a toxic RNA-mediated gain-of-function which leads to aberrant mRNA processing through sequestration of RNA binding proteins such as MBLN1. Hyperlipidaemia is frequently associated with insulin resistance in DM2 patients, but the treatment of these patients is problematic, due to an increased risk of statin-induced myopathy. In our neuromuscular centre, we have noted a 10-fold increase in susceptibly of DM2 patients to statin induced myopathy.We have examined the frequency of the previously published SlCO1B1 risk allele in DM2 patient biopsies and can exclude it as a major cause of increased statin adverse reaction in DM2 patients in Finland. In this study, we compared the global gene expression profiles of muscle biopsies from DM2 patients versus control muscles and expression changes associated with individuals who are on statin medication, with the aim of distinguishing shared affected pathways in a common pathomechanism. The microarray expression profile leads were further analysed in multiple DM2 biopsies by semi-quantitative RT-PCR, with the aim of identifying aberrantly spliced genes among the abnormally expressed genes. We identified a unique set of dysregulated genes. NEDD4, an ubiquitin ligase, was one of the dysregulated genes in DM2 patient muscles and in individuals with statin-induced changes. Our work demonstrates that NEDD4 is abnormally spliced in DM2, which leads to an aberrant isoform of NEDD4 protein being expressed in DM2 patient muscles. PTEN, a known NEDD4 target is increased at the protein level and PTEN accumulates in damaged highly atrophic DM2 muscle fibres. PTEN is linked to lipid metabolism via phosphoinositide signalling and Statins have been shown to cause a general increase in expression of PTEN in normal individuals. We are in the process of overexpressing in cell culture wild-type NEDD4 and DM2 specific splice isoforms and comparing their ability to regulate the turnover of PTEN through ubiquination. Our results suggest that the NEDD4-PTEN ubiquitination pathway becomes dysregulated in DM2 patient's muscles, which may be related to decreased protein turnover in DM2 muscle.
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