title: Analysis of MTMR1 expression and correlation with muscle pathological features in juvenile/adult onset myotonic dystrophy type 1 (DM1) and in myotonic dystrophy type 2 (DM2).
abstract: Among genes abnormally expressed in myotonic dystrophy type1 (DM1), the myotubularin-related 1 gene (MTMR1) was related to impaired muscle differentiation. Therefore, we analyzed MTMR1 expression in correlation with CUG-binding protein1 (CUG-BP1) and muscleblind-like1 protein (MBNL1) steady-state levels and with morphological features in muscle tissues from DM1 and myotonic dystrophy type 2 (DM2) patients. Semi-quantitative RT-PCR for MTMR1 was done on muscle biopsies and primary muscle cultures. The presence of impaired muscle fiber maturation was evaluated using immunochemistry for neural cell adhesion molecule (NCAM), Vimentin and neonatal myosin heavy chain. CUG-BP1 and MBNL1 steady-state levels were estimated by Western blot. RNA-fluorescence in situ hybridization combined with immunochemistry for CUG-BP1, MBNL1 and NCAM were performed on serial muscle sections. An aberrant splicing of MTMR1 and a significant amount of NCAM-positive myofibers were detected in DM1 and DM2 muscle biopsies; these alterations correlated with DNA repeat expansion size only in DM1. CUG-BP1 levels were increased only in DM1 muscles, while MBNL1 levels were similar among DM1, DM2 and controls. Normal and NCAM-positive myofibers displayed no differences either in the amount of ribonuclear foci and the intracellular distribution of MBNL1 and CUG-BP1. In conclusion, an aberrant MTMR1 expression and signs of altered myofiber maturation were documented in both DM1 and in DM2 muscle tissues. The more severe dysregulation of MTMR1 expression in DM1 versus DM2, along with increased CUG-BP1 levels only in DM1 tissues, suggests that the mutual antagonism between MBNL1 and CUG-BP1 on alternative splicing is more unbalanced in DM1.
authors.affiliation: Department of Neuroscience, Center for Neuromuscular Disorders, Catholic University of Sacred Heart, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.forename: Anna
authors.initials: A
authors.lastname: Modoni
authors.forename: Marcella
authors.initials: M
authors.lastname: Masciullo
authors.forename: Teresa
authors.initials: T
authors.lastname: Gidaro
authors.forename: Aldobrando
authors.initials: A
authors.lastname: Broccolini
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Pietro Attilio
authors.initials: PA
authors.lastname: Tonali
authors.forename: Gabriella
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000067879:CELF1 Protein; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; C493663:MBNL1 protein, human; D016601:RNA-Binding Proteins; C116467:MTMR1 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor