title: Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies.
abstract: The prevailing pathomechanistic paradigm for myotonic dystrophy (DM) is that aberrant expression of embryonic/fetal mRNA/protein isoforms accounts for most aspects of the pleiotropic phenotype. To identify aberrant isoforms in skeletal muscle of DM1 and DM2 patients, we performed exon-array profiling and RT-PCR validation on the largest DM sample set to date, including Duchenne, Becker and tibial muscular dystrophy (NMD) patients as disease controls, and non-disease controls. Strikingly, most expression and splicing changes in DM patients were shared with NMD controls. Comparison between DM and NMD identified almost no significant differences. We conclude that DM1 and DM2 are essentially identical for dysregulation of gene expression, and DM expression changes represent a subset of broader spectrum dystrophic changes. We found no evidence for qualitative splicing differences between DM1 and DM2. While some DM-specific splicing differences exist, most of the DM splicing differences were also seen in NMD controls. SSBP3 exon 6 missplicing was observed in all diseased muscle and led to reduced protein. We conclude there is no widespread DM-specific spliceopathy in skeletal muscle and suggest that missplicing in DM (and NMD) may not be the driving mechanism for the muscle pathology, since the same pathways show expression changes unrelated to splicing.
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Linda L
authors: LL
authors: Bachinski
authors: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Keith A
authors: KA
authors: Baggerly
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Valerie L
authors: VL
authors: Neubauer
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Tamara J
authors: TJ
authors: Nixon
authors: Department of Neurology, Tampere University Hospital and Medical School, Tampere, Finland.
authors: Olayinka
authors: O
authors: Raheem
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Mario
authors: M
authors: Sirito
authors: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Anna K
authors: AK
authors: Unruh
authors: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jiexin
authors: J
authors: Zhang
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Lalitha
authors: L
authors: Nagarajan
authors: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors: Lubov T
authors: LT
authors: Timchenko
authors: Neuromuscular Reference Center, Henri Mondor University Hospital, INSERM U955, East-Paris University, Créteil, France.
authors: Guillaume
authors: G
authors: Bassez
authors: Reference Center for Neuromuscular Diseases, Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.
authors: Bruno
authors: B
authors: Eymard
authors: Neuromuscular Disorders Clinic, Neurology Department, Hospital General Vall d'Hebron, Barcelona, Spain.
authors: Josep
authors: J
authors: Gamez
authors: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors: Tetsuo
authors: T
authors: Ashizawa
authors: Division of Child Neurology, Nationwide Childrens Hospital, Ohio State University College of Medicine, Columbus, OH, USA.
authors: Jerry R
authors: JR
authors: Mendell
authors: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Finland; Department of Neurology, Vasa Central Hospital, Finland.
authors: Bjarne
authors: B
authors: Udd
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Graduate Programs in Human & Molecular Genetics, University of Texas at Houston Graduate School in Biomedical Sciences, Houston, TX, USA; Graduate Programs in Genes & Development, University of Texas at Houston Graduate School in Biomedical Sciences, Houston, TX, USA. Electronic address: rkrahe@mdanderson.org.
authors: Ralf
authors: R
authors: Krahe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism; D020967:Myotonic Disorders / Q000235:genetics* / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D055815:Young Adult
chemical_list: D020033:Protein Isoforms
keywords: Aberrant isoform expression; DM1; DM2; Missplicing; Myotonic dystrophy