Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy

Mariko Taniguchi-Ikeda, Kazuhiro Kobayashi, Motoi Kanagawa, Chih Chieh Yu, Kouhei Mori, Tetsuya Oda, Atsushi Kuga, Hiroki Kurahashi, Hasan O. Akman, Salvatore Dimauro, Ryuji Kaji, Toshifumi Yokota, Shin'Ichi Takeda, Tatsushi Toda

Research output: Contribution to journalArticle

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Abstract

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 1-3. 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 α-dystroglycan (α-DG) and laminin binding by α-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia 4, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known 6-8, 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.

Original languageEnglish
Pages (from-to)127-131
Number of pages5
JournalNature
Volume478
Issue number7367
DOIs
Publication statusPublished - 06-10-2011

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Short Interspersed Nucleotide Elements
Walker-Warburg Syndrome
Retroelements
Exons
Antisense Oligonucleotides
3' Untranslated Regions
Messenger RNA
Dystroglycans
Genes
RNA Splicing
Laminin
Therapeutics
Hypercholesterolemia

All Science Journal Classification (ASJC) codes

  • General

Cite this

Taniguchi-Ikeda, M., Kobayashi, K., Kanagawa, M., Yu, C. C., Mori, K., Oda, T., ... Toda, T. (2011). Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature, 478(7367), 127-131. https://doi.org/10.1038/nature10456
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. / Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. In: Nature. 2011 ; Vol. 478, No. 7367. pp. 127-131.
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abstract = "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 1-3. 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 α-dystroglycan (α-DG) and laminin binding by α-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia 4, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known 6-8, 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.",
author = "Mariko Taniguchi-Ikeda and Kazuhiro Kobayashi and Motoi Kanagawa and Yu, {Chih Chieh} and Kouhei Mori and Tetsuya Oda and Atsushi Kuga and Hiroki Kurahashi and Akman, {Hasan O.} and Salvatore Dimauro and Ryuji Kaji and Toshifumi Yokota and Shin'Ichi Takeda and Tatsushi Toda",
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Taniguchi-Ikeda, M, Kobayashi, K, Kanagawa, M, Yu, CC, Mori, K, Oda, T, Kuga, A, Kurahashi, H, Akman, HO, Dimauro, S, Kaji, R, Yokota, T, Takeda, SI & Toda, T 2011, 'Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy', Nature, vol. 478, no. 7367, pp. 127-131. https://doi.org/10.1038/nature10456

Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. / 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.

In: Nature, Vol. 478, No. 7367, 06.10.2011, p. 127-131.

Research output: Contribution to journalArticle

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T1 - Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy

AU - Taniguchi-Ikeda, Mariko

AU - Kobayashi, Kazuhiro

AU - Kanagawa, Motoi

AU - Yu, Chih Chieh

AU - Mori, Kouhei

AU - Oda, Tetsuya

AU - Kuga, Atsushi

AU - Kurahashi, Hiroki

AU - Akman, Hasan O.

AU - Dimauro, Salvatore

AU - Kaji, Ryuji

AU - Yokota, Toshifumi

AU - Takeda, Shin'Ichi

AU - Toda, Tatsushi

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N2 - 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 1-3. 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 α-dystroglycan (α-DG) and laminin binding by α-DG. Moreover, we observe exon-trapping in other SVA insertions associated with disease (hypercholesterolemia 4, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, although splicing into SVA is known 6-8, 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.

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