Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/93822
Title: Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB
Authors: Krainer, Adrian R.
Chew, Shern L.
Khoo, Bernard
Roca, Xavier
Keywords: DRNTU::Science::Biological sciences::Molecular biology
Issue Date: 2007
Source: Khoo, B., Roca, X., Chew, S. L., & Krainer, A. R. (2007). Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB. BMC Molecular Biology, 8(3).
Series/Report no.: BMC molecular biology
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, APOB87SKIP27. Conclusion: The induction of APOB87SKIP27 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.
URI: https://hdl.handle.net/10356/93822
http://hdl.handle.net/10220/6875
DOI: http://dx.doi.org/10.1186/1471-2199-8-3
Rights: © 2007 BioMed Central. This paper was published in BMC Molecular Biology and is made available as an electronic reprint (preprint) with permission of BioMed Central. The paper can be found at the following DOI: http://dx.doi.org/10.1186/1471-2199-8-3. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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