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 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.

Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2+5G > C mutation in ABCA1 gene / S., Altilia; L., Pisciotta; R., Garuti; Tarugi, Patrizia Maria; A., Cantafora; L., Calabresi; J., Tagliabue; S., Maccari; F., Bernini; I., Zanotti; C., Vergani; S., Bertolini; CALANDRA BUONAURA, Sebastiano. - In: JOURNAL OF LIPID RESEARCH. - ISSN 0022-2275. - STAMPA. - 44(2003), pp. 254-264.

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