The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients. Issue 10 (8th July 2008)

• Record Type: Journal Article
• Authors: Botta, A; Rinaldi, F; Catalli, C; Vergani, L; Bonifazi, E; Romeo, V; Loro, E; Viola, A; Angelini, C; Novelli, G
• Is Part Of: Journal of medical genetics. Volume 45:Issue 10(2008)
• Page Start: 639
• Page End: 646
• Publication Date: 2008-07-08
• Subjects: Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmg.2008.058909
• Languages: English
• ISSNs: 1468-6244

Abstract

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.