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Abnormal apolipoprotein B pre-mRNA splicing in patients with familial hypobetalipoproteinaemia
  1. Enza Di Leo1,
  2. Lucia Magnolo1,
  3. Sandra Lancellotti1,
  4. Lory Crocè2,
  5. Luca Visintin2,
  6. Claudio Tiribelli2,
  7. Stefano Bertolini3,
  8. Sebastiano Calandra1,
  9. Patrizia Tarugi1
  1. 1Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
  2. 2Liver Research Center, AREA Science Park, Basovizza, University of Trieste, Trieste, Italy
  3. 3Department of Internal Medicine, University of Genova, Genova, Italy
  1. Correspondence to:
 Professor P Tarugi
 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, I-41100 Modena, Italy; tarugi{at}


Background: Familial hypobetalipoproteinaemia (FHBL) is a codominant disorder characterised by fatty liver and reduced plasma levels of low-density lipoprotein (LDL) and its protein constituent apolipoprotein B (apoB). FHBL is linked to the APOB gene in some but not all known cases. In a group of 59 patients with FHBL 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 on apoB pre-mRNA splicing.

Methods: ApoB mRNA was analysed 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, an apoB mRNA devoid of exon 25 was identified, predicted to encode a truncated peptide of 1260 amino acids. The analysis of minigene transcripts in COS-1 cells showed that the 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.

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

  • apoB, apolipoprotein B
  • FHBL, familial hypobetalipoproteinaemia
  • LDL, low-density lipoprotein
  • LDL-C, LDL-cholesterol
  • PCR, polymerase chain reaction
  • VLDL, very-low-density lipoproteins

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  • Published Online First 8 December 2006

  • Competing interests: None.

  • Informed consent was obtained for publication of patients’ details in this report.