title: DM1 CTG expansions affect insulin receptor isoforms expression in various tissues of transgenic mice.
abstract: Myotonic dystrophy (DM1) is a dominant autosomal multisystemic disorder caused by the expansion of an unstable CTG trinucleotide repeat in the 3' untranslated region of the DMPK gene. Nuclear accumulation of the enlarged CUG-containing DMPK transcripts has a deleterious effect on the regulation of alternative splicing of some RNAs and has a central role in causing the symptoms of DM1. In particular, Insulin Receptor (IR) mRNA splicing defects have been observed in the muscle of DM1 patients. In this study, we have investigated IR splicing in insulin-responsive tissues (i.e. skeletal muscles, adipose tissue, liver) and pancreas and we have studied glucose metabolism in mice carrying the human genomic DM1 region with expanded (>350 CTG) or normal (20 CTG) repeats and in wild-type mice. Mice carrying DM1 expansions displayed a tissue- and age-dependent abnormal regulation of IR mRNA splicing in all the tissues that we investigated. Furthermore, these mice showed a basal hyperglycemia and glucose intolerance which disappeared with age. Our findings show that deregulation of IR splicing due to the DM1 mutation can occur in different mouse tissues, suggesting that CTG repeat expansions might also result in IR misplicing not only in muscles but also in other tissues in DM1 patients.
authors.affiliation: INSERM, U781, Hôpital Necker-Enfants Malades, Université René Descartes Paris V, 149 rue de Sèvres, 75743 Paris cedex 15, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Guiraud-Dogan
authors.forename: Aline
authors.initials: A
authors.lastname: Huguet
authors.forename: Mário
authors.initials: M
authors.lastname: Gomes-Pereira
authors.forename: Edith
authors.initials: E
authors.lastname: Brisson
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bassez
authors.forename: Claudine
authors.initials: C
authors.lastname: Junien
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
mesh_terms: D000375:Aging; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D009928:Organ Specificity; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C585517:DMPK protein, human; C585516:DMPK protein, mouse; D007328:Insulin; D050505:Mutant Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011972:Receptor, Insulin; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose