Abstract
Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis.
Highlights
Myotonic dystrophies are dominantly inherited multisystemic disorders characterized by muscle weakness, myotonia, CNS involvement and cataracts.Two types of DM have been described
The Exon Array Analyzer (EAA) software analysis predicted 273 Alternative splicing (AS) events distributed on 218 genes, with Splice Index (SI) .+0.5 or,0.5 and p-value,0.05 (Table S3)
46 AS splicing events were already annotated in AStalavista or in the UCSC Genome Browser, albeit most of them not in this specific disease context: 27 were cassette exons, 6 were intron retentions, 10 were bleeding exons, while 3 events were not classified as AS, but as alternative promoter usage [39]
Summary
Myotonic dystrophies are dominantly inherited multisystemic disorders characterized by muscle weakness, myotonia, CNS involvement and cataracts.Two types of DM have been described. Myotonic dystrophy type 1 (DM1) or Steinert’s disease (DM1, OMIM 160900) is one of the most common forms of muscular dystrophy in adults with a prevalence of 1/8000 worldwide [1]. It is caused by an expanded (CTG)n repeat in the 3’ untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene [2,3,4]. Myotonic dystrophy type 2 (DM2, OMIM 602688) displays a prevalently proximal impairment and milder clinical symptoms than DM1 It is caused by the expansion of a tetranucleotidic repetition (CCTG)n in the first intron of the CCHC-type zinc finger, nucleic acid binding protein (CNBP) gene [5]
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