Abstract:
:Secondary alterations in splicing have been reported to produce semi-functional mRNA from several nonsense mutations in the dystrophin gene. Disruptions of exonic splicing enhancers by single nucleotide changes are thought to underlie such alterations. The precise frequencies of such nonsense mutation-dependent splicing alterations, however, remain unknown. Here we analyzed the splicing patterns of dystrophin mRNA in lymphocytes from 38 patients with dystrophinopathies due to nonsense mutations in the dystrophin gene. In seven of the cases (18%), we observed partial skipping of the nonsense-encoding exon. Two of the seven cases, however, exhibited complex activation of a nonsense mutation-created splice site, which resulted in the generation of novel transcripts. Examination of cis-regulatory splicing elements through calculation of splicing probability scores and identification of potential splicing enhancer or silencer sequences failed to disclose a single cause for exon skipping. Remarkably, individual differences in splicing patterns were observed for cells from patients with identical nonsense mutations (C.5899C>T). Although five cases produced semi-functional dystrophin mRNAs, only one of these exhibited a mild clinical course. These results provide important insights about targets for exon skipping induced by candidate antisense oligonucleotides and for ribosomal read-through of nonsense mutations.
journal_name
Ann Hum Genetjournal_title
Annals of human geneticsauthors
Nishiyama A,Takeshima Y,Zhang Z,Habara Y,Tran TH,Yagi M,Matsuo Mdoi
10.1111/j.1469-1809.2008.00468.xsubject
Has Abstractpub_date
2008-11-01 00:00:00pages
717-24issue
Pt 6eissn
0003-4800issn
1469-1809pii
AHG468journal_volume
72pub_type
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