title: Gene expression analysis in myotonic dystrophy: indications for a common molecular pathogenic pathway in DM1 and DM2.
abstract: An RNA gain-of-function of expanded transcripts is the most accredited molecular mechanism for myotonic dystrophy type 1 (DM1) and 2 (DM2). To disclose molecular parallels and divergences in pathogenesis of both disorders, we compared the expression profile of muscle biopsies from DM1 and DM2 patients to controls. DM muscle tissues showed a reduction in the major skeletal muscle chloride channel (CLCN1) and transcription factor Sp1 transcript levels and an abnormal processing of the CLCN1 and insulin receptor (IR) pre-mRNAs. No essential differences were observed in the muscle blind-like gene (MBNL1) and CUG binding protein 1 (CUGBP1) transcript levels as well as in the splicing pattern of the myotubularin-related 1 (MTMR1) gene. Macroarray analysis of 96 neuroscience-related genes revealed a considerable similar expression profile between the DM samples, reflective of a common muscle pathology origin. Using a twofold threshold, we found six misregulated genes important in calcium and potassium metabolism and in mitochondrial functions. Our results indicate that the DM1 and DM2 overlapping clinical phenotypes may derive from a common trans acting mechanism that traps and influences shared genes and proteins. An RNA gain-of-function of expanded transcripts is the most accredited molecular mechanism for myotonic dystrophy type 1 (DM1) and 2 (DM2). To disclose molecular parallels and divergences in pathogenesis of both disorders, we compared the expression profile of muscle biopsies from DM1 and DM2 patients to controls. DM muscle tissues showed a reduction in the major skeletal muscle chloride channel (CLCN1) and transcription factor Sp1 transcript levels and an abnormal processing of the CLCN1 and insulin receptor (IR) pre-mRNAs. No essential differences were observed in the muscle blind-like gene (MBNL1) and CUG binding protein 1 (CUGBP1) transcript levels as well as in the splicing pattern of the myotubularin-related 1 (MTMR1) gene. Macroarray analysis of 96 neuroscience-related genes revealed a considerable similar expression profile between the DM samples, reflective of a common muscle pathology origin. Using a twofold threshold, we found six misregulated genes important in calcium and potassium metabolism and in mitochondrial functions. Our results indicate that the DM1 and DM2 overlapping clinical phenotypes may derive from a common trans acting mechanism that traps and influences shared genes and proteins.
authors: Department of Biopathology, Tor Vergata University of Rome, Rome, Italy. abottait@yahoo.it
authors: Annalisa
authors: A
authors: Botta
authors: Laura
authors: L
authors: Vallo
authors: Fabrizio
authors: F
authors: Rinaldi
authors: Emanuela
authors: E
authors: Bonifazi
authors: Francesca
authors: F
authors: Amati
authors: Michela
authors: M
authors: Biancolella
authors: Stefano
authors: S
authors: Gambardella
authors: Enzo
authors: E
authors: Mancinelli
authors: Corrado
authors: C
authors: Angelini
authors: Giovanni
authors: G
authors: Meola
authors: Giuseppe
authors: G
authors: Novelli
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D001706:Biopsy; D018118:Chloride Channels / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D007473:Ion Channels; C116467:MTMR1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor
references: Nat Genet. 2001 Sep;29(1):40-7
references: 11528389
references: EMBO J. 2000 Sep 1;19(17):4439-48
references: 10970838
references: Genomics. 1994 Oct;23(3):628-34
references: 7851891
references: Neuromuscul Disord. 2005 Jan;15(1):5-16
references: 15639115
references: J Clin Invest. 1982 Feb;69(2):358-67
references: 6276440
references: Hum Mol Genet. 2002 Apr 1;11(7):805-14
references: 11929853
references: Science. 2004 Jan 16;303(5656):383-7
references: 14657503
references: Acta Physiol Scand. 1996 Mar;156(3):355-67
references: 8729696
references: Neurosci Lett. 2000 Dec 8;295(3):93-6
references: 11090982
references: Neurology. 2000 Dec 12;55(11):1697-703
references: 11113225
references: Science. 1989 Aug 11;245(4918):640-3
references: 2562787
references: Neuromuscul Disord. 2001 Jul;11(5):485-8
references: 11404122
references: Cell. 1992 Feb 21;68(4):799-808
references: 1310900
references: Hum Mol Genet. 2001 Sep 15;10(19):2165-70
references: 11590133
references: J Neurol. 2004 Oct;251(10):1173-82
references: 15503094
references: J Gen Physiol. 2007 Jan;129(1):79-94
references: 17158949
references: Prog Nucleic Acid Res Mol Biol. 1990;38:37-89
references: 2158121
references: Acta Biochim Pol. 2000;47(3):705-23
references: 11310971
references: Nat Genet. 1998 Jun;19(2):196-8
references: 9620781
references: Neurology. 1996 Sep;47(3):711-7
references: 8797469
references: BMC Bioinformatics. 2003 Jun 24;4:26
references: 12823867
references: Mol Cell Biol. 2001 Feb;21(4):1285-96
references: 11158314
references: Neuromuscul Disord. 1999 Jan;9(1):19-27
references: 10063831
references: Science. 2003 Dec 12;302(5652):1978-80
references: 14671308
references: J Biol Chem. 2004 Mar 26;279(13):13129-39
references: 14722059
references: Biochim Biophys Acta. 2006 Mar;1762(3):329-34
references: 16376058
references: Annu Rev Biophys Biomol Struct. 2000;29:411-38
references: 10940254
references: J Physiol. 2000 Dec 15;529 Pt 3:533-9
references: 11118488
references: Hum Mol Genet. 2006 Jun 1;15(11):1808-15
references: 16624843
references: Am J Hum Genet. 2004 Jun;74(6):1309-13
references: 15114529
references: Science. 1992 Mar 6;255(5049):1253-5
references: 1546325
references: FEBS Lett. 1997 Sep 8;414(2):258-62
references: 9315697
references: Mol Cell. 2002 Jul;10(1):45-53
references: 12150906
references: Hum Mol Genet. 2005 Aug 1;14(15):2189-200
references: 15972723
references: Science. 1998 May 1;280(5364):737-41
references: 9563950
references: Biochemistry. 1994 Sep 6;33(35):10809-14
references: 8075083
references: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R162-9
references: 16987879
references: Neurology. 1994 Aug;44(8):1448-52
references: 8058147
references: Hum Mol Genet. 2001 Sep 15;10(19):2143-55
references: 11590131
references: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4252-7
references: 15755808
references: Diagn Mol Pathol. 2004 Sep;13(3):164-6
references: 15322428
references: Hum Mol Genet. 2004 Dec 15;13(24):3079-88
references: 15496431
references: J Physiol. 1990 Jun;425:391-405
references: 1698978
references: Hum Mol Genet. 2005 Jun 1;14(11):1539-47
references: 15843400
references: Science. 2001 Aug 3;293(5531):864-7
references: 11486088
references: Science. 1992 Mar 6;255(5049):1256-8
references: 1546326
references: Hum Mol Genet. 2002 Sep 15;11(19):2297-307
references: 12217958
references: J Clin Invest. 1997 Sep 15;100(6):1440-7
references: 9294109
references: Science. 1993 Apr 9;260(5105):235-8
references: 8469976
references: Biochim Biophys Acta. 1990 Nov 14;1096(1):14-9
references: 2176547
references: Nucleic Acids Res. 2001 Jul 1;29(13):2766-71
references: 11433021
references: J Histochem Cytochem. 1999 Mar;47(3):383-92
references: 10026240
references: Genomics. 1993 Nov;18(2):340-8
references: 8288237
references: Acta Neurol Scand. 1989 Nov;80(5):419-24
references: 2589008
references: J Neurol Sci. 1993 Jun;116(2):193-200
references: 8336166
references: Muscle Nerve. 1979 May-Jun;2(3):165-72
references: 503103
references: Trends Genet. 2004 Oct;20(10):506-12
references: 15363905
references: Nucleic Acids Res. 1996 Nov 15;24(22):4407-14
references: 8948631
references: Diagn Mol Pathol. 1998 Jun;7(3):135-7
references: 9836067
references: Mol Cell. 2002 Jul;10(1):35-44
references: 12150905