Abnormal apolipoprotein B pre-mRNA splicing in patients with familial hypobetalipoproteinaemia.

Abstract

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.

• Authors: Enza Di Leo, Lucia Magnolo, Sandra Lancellotti, Lory Crocè, Luca Visintin, Claudio Tiribelli, Stefano Bertolini, Sebastiano Calandra, Patrizia Tarugi
• Journal: Journal of medical genetics (J Med Genet) Vol. 44 Issue 3 Pg. 219-24 (Mar 2007) ISSN: 1468-6244 [Electronic] England
• PMID: 17158591 (Publication Type: Letter, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins B
• Lipids
• Lipoproteins
• RNA Precursors
• RNA Splice Sites

Topics

• Adult
• Animals
• Apolipoproteins B (chemistry, deficiency, genetics, physiology)
• COS Cells
• Child
• Chlorocebus aethiops
• DNA Mutational Analysis
• Fatty Liver (etiology, metabolism)
• Female
• Genes, Synthetic
• Genotype
• Humans
• Hypobetalipoproteinemia, Familial, Apolipoprotein B (blood, complications, genetics)
• Introns (genetics)
• Lipids (blood)
• Lipoproteins (blood)
• Liver (metabolism, pathology)
• Male
• RNA Precursors (genetics)
• RNA Splice Sites (genetics)
• RNA Splicing (genetics)
• Transfection