Publication Date:
2011-10-08
Description:
Fukuyama muscular dystrophy (FCMD; MIM253800), one of the most common autosomal recessive disorders in Japan, was the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposon into a causative gene. In FCMD, the SVA insertion occurs in the 3' untranslated region (UTR) of the fukutin gene. The pathogenic mechanism for FCMD is unknown, and no effective clinical treatments exist. Here we show that aberrant messenger RNA (mRNA) splicing, induced by SVA exon-trapping, underlies the molecular pathogenesis of FCMD. Quantitative mRNA analysis pinpointed a region that was missing from transcripts in patients with FCMD. This region spans part of the 3' end of the fukutin coding region, a proximal part of the 3' UTR and the SVA insertion. Correspondingly, fukutin mRNA transcripts in patients with FCMD and SVA knock-in model mice were shorter than the expected length. Sequence analysis revealed an abnormal splicing event, provoked by a strong acceptor site in SVA and a rare alternative donor site in fukutin exon 10. The resulting product truncates the fukutin carboxy (C) terminus and adds 129 amino acids encoded by the SVA. Introduction of antisense oligonucleotides (AONs) targeting the splice acceptor, the predicted exonic splicing enhancer and the intronic splicing enhancer prevented pathogenic exon-trapping by SVA in cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of alpha-dystroglycan (alpha-DG) and laminin binding by alpha-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known, we have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412178/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412178/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Taniguchi-Ikeda, Mariko -- Kobayashi, Kazuhiro -- Kanagawa, Motoi -- Yu, Chih-chieh -- Mori, Kouhei -- Oda, Tetsuya -- Kuga, Atsushi -- Kurahashi, Hiroki -- Akman, Hasan O -- DiMauro, Salvatore -- Kaji, Ryuji -- Yokota, Toshifumi -- Takeda, Shin'ichi -- Toda, Tatsushi -- T32 AR056993/AR/NIAMS NIH HHS/ -- England -- Nature. 2011 Oct 5;478(7367):127-31. doi: 10.1038/nature10456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21979053" target="_blank"〉PubMed〈/a〉
Keywords:
3' Untranslated Regions/genetics
;
Alternative Splicing/drug effects/*genetics
;
Animals
;
Disease Models, Animal
;
Dystroglycans/metabolism
;
Exons/*genetics
;
Gene Knock-In Techniques
;
Glycosylation
;
Humans
;
Introns/genetics
;
Japan
;
Laminin/metabolism
;
Membrane Proteins/genetics/metabolism
;
Mice
;
Molecular Sequence Data
;
Mutagenesis, Insertional/drug effects/genetics
;
Oligonucleotides, Antisense/genetics/pharmacology/therapeutic use
;
RNA Isoforms/genetics
;
RNA Splice Sites/genetics
;
Retroelements/*genetics
;
Walker-Warburg Syndrome/*genetics/*pathology/therapy
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
