Gene expression analysis in myotonic dystrophy: indications for a common molecular pathogenic pathway in DM1 and DM2.
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.
Botta
Annalisa
A
Department of Biopathology, Tor Vergata University of Rome, Rome, Italy. abottait@yahoo.it
Vallo
Laura
L
Rinaldi
Fabrizio
F
Bonifazi
Emanuela
E
Amati
Francesca
F
Biancolella
Michela
M
Gambardella
Stefano
S
Mancinelli
Enzo
E
Angelini
Corrado
C
Meola
Giovanni
G
Novelli
Giuseppe
G
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*
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
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