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.