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Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB

Khoo, B; Roca, X; Chew, SL; Krainer, AR; (2007) Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB. BMC MOL BIOL , 8 , Article 3. 10.1186/1471-2199-8-3. Green open access

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Abstract

Background: Apolipoprotein B (APOB) is an integral part of the LDL, VLDL, IDL, Lp(a) and chylomicron lipoprotein particles. The APOB pre-mRNA consists of 29 constitutively-spliced exons. APOB exists as two natural isoforms: the full-length APOB100 isoform, assembled into LDL, VLDL, IDL and Lp(a) and secreted by the liver in humans; and the C-terminally truncated APOB48, assembled into chylomicrons and secreted by the intestine in humans. Down-regulation of APOB100 is a potential therapy to lower circulating LDL and cholesterol levels.Results: We investigated the ability of 2' O-methyl RNA antisense oligonucleotides (ASOs) to induce the skipping of exon 27 in endogenous APOB mRNA in HepG2 cells. These ASOs are directed towards the 5' and 3' splice-sites of exon 27, the branch-point sequence (BPS) of intron 26-27 and several predicted exonic splicing enhancers within exon 27. ASOs targeting either the 5' or 3' splice-site, in combination with the BPS, are the most effective. The splicing of other alternatively spliced genes are not influenced by these ASOs, suggesting that the effects seen are not due to non-specific changes in alternative splicing. The skip 27 mRNA is translated into a truncated isoform, APOB87(SKIP27).Conclusion: The induction of APOB87(SKIP27) expression in vivo should lead to decreased LDL and cholesterol levels, by analogy to patients with hypobetalipoproteinemia. As intestinal APOB mRNA editing and APOB48 expression rely on sequences within exon 26, exon 27 skipping should not affect APOB48 expression unlike other methods of down-regulating APOB100 expression which also down-regulate APOB48.

Type: Article
Title: Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/1471-2199-8-3
Publisher version: http://www.biomedcentral.com/1471-2199/8/3
Language: English
Additional information: © 2007 Khoo et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: TRUNCATED APOLIPOPROTEIN-B, NONSENSE-MEDIATED DECAY, FAMILIAL HYPOBETALIPOPROTEINEMIA, SECONDARY STRUCTURE, MAMMALIAN-CELLS, GENE-EXPRESSION, IN-VIVO, IDENTIFICATION, PROTEIN, ENHANCERS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/105382
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