Hypobetalipoproteinaemia and truncated forms of human apolipoprotein B

Abstract

A new variant of human apolipoprotein B has been identified in a subject with decreased low density lipoprotein cholesterol and apolipoprotein B concentrations. Although no clinical signs of fat malabsorption were observed the subject was diagnosed, on the basis of his low cholesterol and apolipoprotein B level, as having hypobetalipoproteinaemia.

The variant of apolipoprotein B was first identified by Western blot analysis. The analysis revealed an abnormal low molecular weight form of apolipoprotein B as well as normal apolipoprotein B-100 indicating that the subject was heterozygous for a truncated form of apolipoprotein B. The new variant (apo B-32) was a result of a C→T transition at nucleotide 4548 in exon 26 of the apolipoprotein B gene. This mutation changes a CAG codon which codes for glutamine into a TAG stop codon resulting in translation of a truncated apolipoprotein B protein approximately 32% the length of normal apolipoprotein B-100.

Although only 32% of the length of apolipoprotein B-100, apo B-32 was still capable of forming lipoprotein particles as indicated by its presence in both the low density and high density lipoprotein fractions. This density distribution is unique since apo B-32 is the shortest known truncated apolipoprotein B to be found in the low density lipoprotein fraction. This finding clearly indicates that the region of apo B-32 is important in the lipid binding characteristics of apolipoprotein B-100. The binding of apo B-32 to heparin confirmed three heparin binding sites previously predicted to be in the amino-terminal 30% of apolipoprotein B-100.

Isolated lipoproteins formed from apo B-32 appeared to be similar to high density lipoproteins in size and composition. However, unlike high density lipoproteins, the apo B-32 lipoproteins in plasma were partially precipitated by polyanionlcation reagents normally used to precipitate very low density and low density lipoproteins. The presence of both apolipoproteins Al and E on the apo B-32 lipoproteins suggested that apolipoprotein Al or E may mediate the metabolism of apo B-32 since apo B-32 does not posses the receptor binding region for the low density lipoprotein receptor.

Four further subjects were identified as having reduced low density lipoprotein and apolipoprotein B concentrations. However a lack of any truncated apolipoprotein B in their plasma made it difficult to link their hypobetalipoproteinaemia with the apolipoprotein B gene. The cause of the hypobetalipoproteinaemia in these subjects remains uncharacterised although future linkage analysis studies in these individuals and family members will at least establish whether their hypobetalipoproteinaemia is related to the apo B gene.