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Abnormal apolipoprotein b pre-mrna splicing in patients with familial hypobetalipoproteinemia
  1. Enza Di Leo
  1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
    1. Lucia Magnolo
    1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
      1. Sandra Lancellotti
      1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
        1. Lory Crocè
        1. Liver Research Center, Department of BBCM, University of Trieste, Italy
          1. Luca Visintin
          1. Liver Research Center, Department of BBCM, University of Trieste, Italy
            1. Claudio Tiribelli
            1. Liver Research Center, Department of BBCM, University of Trieste, Italy
              1. Stefano Bertolini
              1. Department of Internal Medicine, University of Genova, Italy
                1. Sebastiano Calandra
                1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy
                  1. Patrizia Tarugi (tarugi{at}unimo.it)
                  1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy

                    Abstract

                    Background: Familial Hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by fatty liver and reduced plasma levels of low density lipoprotein (LDL) and its protein constituent apolipoprotein B (apoB). FHBL is linked to APOB gene in some but not all known cases. In a group of 59 FHBL patients genotyped for APOB gene mutations we found three novel splice site mutations: c.904+4A>G in intron 8, c.3843-2A>G in intron 24 and c.4217-1G>T in intron 25.

                    Objective: To assess the effects of these mutations of apoB pre-mRNA splicing.

                    Methods: We analysed apoB mRNA in the liver of one proband and in cells expressing APOB minigenes harbouring the mutations found in the other probands.

                    Results: In the liver of the c.3843-2A>G carrier we identified an apoB mRNA devoid of exon 25, predicted to encode a truncated peptide of 1260 amino acids. The analysis of minigene transcripts in COS-1 cells showed that c.904+4A>G mutation caused the formation of an mRNA devoid of exon 8,predicted to encode a short apoB of 247 amino acids. The minigene harbouring the c.4217-1G>T mutation in intron 25 generated an mRNA in which exon 25 joined to a partially deleted exon 26, resulting from the activation of an acceptor site in exon 26; this mRNA is predicted to encode a truncated protein of 1380 amino acids. All these truncated apoBs were not secreted as constituents of plasma lipoproteins.

                    Conclusions: These findings demonstrate the pathogenic effect of rare splice site mutations of APOB gene found in FHBL.

                    • Apolipoprotein B gene
                    • Familial hypobetalipoproteinemia
                    • Intronic mutations
                    • Splicing defects
                    • Truncated apolipoprotein B

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