title: Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2.
abstract: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.
authors.affiliation: Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, Milan, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Cardani
authors.affiliation: Department of Neurology, University of Milan, IRCCS-Policlinico San Donato, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bugiardini
authors.affiliation: Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Renna
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Graziano
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Research Laboratories - Molecular Biology, IRCCS-Policlinico San Donato, Milan, Italy.
authors.forename: Rea
authors.initials: R
authors.lastname: Valaperta
authors.affiliation: IRCCS-Neuromed, Pozzilli, Isernia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Botta
authors.affiliation: Laboratory of Muscle Histopathology and Molecular Biology, IRCCS-Policlinico San Donato, Milan, Italy ; Department of Neurology, University of Milan, IRCCS-Policlinico San Donato, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000067879:CELF1 Protein; D016022:Case-Control Studies; D018118:Chloride Channels / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009223:Myotonic Dystrophy / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D055815:Young Adult
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; C086321:CLC-1 channel; C433227:CNBP protein, human; D018118:Chloride Channels; C493663:MBNL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506943:ATP2A1 protein, human