J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on February 1, 2003

Papers In Press, published online ahead of print November 4, 2002
J. Lipid Res., doi:10.1194/jlr.M200248-JLR200
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Submitted on June 26, 2002
Revised on October 23, 2002
Accepted on October 23, 2002

Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G>C mutation in ABCA1 gene

Serena Altilia, Livia Pisciotta, Rita Garuti, Patrizia Tarugi, Alfredo Cantafora, Laura Calabresi, Jacopo Tagliabue, Sergio Maccari, Franco Bernini, Ilaria Zanotti, Carlo Vergani, Stefano Bertolini, and Sebastiano Calandra

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena I-41100

Corresponding Author: sebcal{at}unimo.it

Two point mutations of ABCA1 gene were found in a patient with Tangier disease (TD): i) G>C in intron 2 (IVS2 +5G>C) and ii) c.844 C>T in exon 9 (R282X). The IVS2 +5G>C mutation was also found in the brother of another deceased TD patient, but not in 78 controls and 33 subjects with low HDL. The IVS2 +5G>C mutation disrupts ABCA1 pre-mRNA splicing in fibroblasts, leading to three abnormal mRNAs: devoid of exon 2 (Ex2-/mRNA), exon 4 (Ex4-/mRNA) or both these exons (Ex2-/Ex4-/mRNA), each containing a translation initiation site. These mRNAs are expected either not to be translated or to generate short peptides. To investigate the in vitro effect of IVS2 +5G>C mutation, we constructed two ABCA1 minigenes encompassing Ex1-Ex3 region, one with wild type (WTgene) and the other with mutant (MTgene) intron 2. These minigenes were transfected into COS1 and NIH3T3, two cell lines with a different ABCA1 gene expression. In COS1 cells WTgene pre-mRNA was spliced correctly, while the splicing of MTgene pre-mRNA resulted in Ex2-/mRNA. In NIH3T3 no splicing of MTgene pre-mRNA was observed, whereas WTgene pre-mRNA was spliced correctly. These results stress the complexity of ABCA1 pre-mRNA splicing in the presence of splice site mutations.


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