Background: Myotonic dystrophy type 1 is caused by an unstable (CTG)n repetition located in the 3 ' UTR of the DM protein kinase gene (DMPK). Untranslated expanded DMPK transcripts are retained in ribonuclear foci which sequester CUG-binding proteins essential for the maturation of pre-mRNAs. Aim: To investigate the effects of CTG expansion length on three molecular parameters associated with the DM1 muscle pathology: (1) the expression level of the DMPK gene; (2) the degree of splicing misregulation; and (3) the number of ribonuclear foci. Methods: Splicing analysis of the IR, MBNL1, c-TNT and CLCN1 genes, RNA-FISH experiments and determination of the DMPK expression on muscle samples from DM1 patients with an expansion below 500 repetitions (n= 6), DM1 patients carrying a mutation above 1000 CTGs (n= 6), and from controls (n= 6). Results: The level of aberrant splicing of the IR, MBNL1, c-TNT and CLCN1 genes is different between the two groups of DM1 muscle samples and correlates with the CTG repeat length. RNA-FISH analysis revealed that the number of ribonuclear foci in DM1 muscle sections increases in patients with a higher (CTG) n number. No relationships were found between the expression level of the DMPK gene transcript and average expansion sizes. Conclusion: The CTG repeat length plays a key role in the extent of splicing misregulation and foci formation, thus providing a useful link between the genotype and the molecular cellular phenotype in DM1.

Botta, A., Rinaldi, F., Catalli, C., Vergani, L., Bonifazi, E., Romeo, V., et al. (2008). The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients. JOURNAL OF MEDICAL GENETICS, 45(10), 639-646 [10.1136/jmg.2008.058909].

The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients

BOTTA, ANNALISA;NOVELLI, GIUSEPPE
2008-07

Abstract

Background: Myotonic dystrophy type 1 is caused by an unstable (CTG)n repetition located in the 3 ' UTR of the DM protein kinase gene (DMPK). Untranslated expanded DMPK transcripts are retained in ribonuclear foci which sequester CUG-binding proteins essential for the maturation of pre-mRNAs. Aim: To investigate the effects of CTG expansion length on three molecular parameters associated with the DM1 muscle pathology: (1) the expression level of the DMPK gene; (2) the degree of splicing misregulation; and (3) the number of ribonuclear foci. Methods: Splicing analysis of the IR, MBNL1, c-TNT and CLCN1 genes, RNA-FISH experiments and determination of the DMPK expression on muscle samples from DM1 patients with an expansion below 500 repetitions (n= 6), DM1 patients carrying a mutation above 1000 CTGs (n= 6), and from controls (n= 6). Results: The level of aberrant splicing of the IR, MBNL1, c-TNT and CLCN1 genes is different between the two groups of DM1 muscle samples and correlates with the CTG repeat length. RNA-FISH analysis revealed that the number of ribonuclear foci in DM1 muscle sections increases in patients with a higher (CTG) n number. No relationships were found between the expression level of the DMPK gene transcript and average expansion sizes. Conclusion: The CTG repeat length plays a key role in the extent of splicing misregulation and foci formation, thus providing a useful link between the genotype and the molecular cellular phenotype in DM1.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/03 - Genetica Medica
English
Con Impact Factor ISI
cytosine; guanine; insulin receptor; muscle chloride channel 1 protein; muscle protein; muscleblind like 1 protein; myotonic dystrophy protein kinase; thymine; troponin T; unclassified drug; adolescent; adult; article; clinical article; controlled study; fluorescence in situ hybridization; gene expression; gene mutation; genetic association; genetic transcription; human; human tissue; muscle biopsy; myotonic dystrophy; myotonic dystrophy type 1; nucleic acid structure; nucleotide repeat; nucleotide sequence; priority journal; risk factor; RNA analysis; RNA splicing; Adolescent; Adult; Exons; Gene Expression; Humans; In Situ Hybridization, Fluorescence; Middle Aged; Muscle, Skeletal; Myotonic Dystrophy; Protein-Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA Splicing; Trinucleotide Repeat Expansion
Botta, A., Rinaldi, F., Catalli, C., Vergani, L., Bonifazi, E., Romeo, V., et al. (2008). The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients. JOURNAL OF MEDICAL GENETICS, 45(10), 639-646 [10.1136/jmg.2008.058909].
Botta, A; Rinaldi, F; Catalli, C; Vergani, L; Bonifazi, E; Romeo, V; Loro, E; Viola, A; Angelini, C; Novelli, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/38332
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