Donor splice mutation generates a lipid-associated apolipoprotein B-27.6 in a patient with homozygous hypobetalipoproteinemia.

We report the characterization of a new truncated apolipoprotein (apo) B, originally identified in the plasma of a homozygous proband and three heterozygous family members with hypobetalipoproteinemia. Using Western blotting, the truncated apoB species was estimated to be 27.5% the size of apoB-100. After fast protein liquid chromatography of plasma from the proband (CD) and mother (OS), the truncated apoB was eluted with particles whose sizes were between normal low and high density lipoproteins. Sequencing of exons 21-24, including the intron-exon boundaries, revealed a T-->C transition at +2 of intron 24, homozygous in CD and heterozygous in OS, thus disrupting the 5' donor splice site and interrupting the translation of serine. On the basis of this, the truncated protein was estimated to be approximately apoB-27.6. The reason for this approximation is that splice-junction mutations can generate different mRNA transcripts, and the truncated protein might represent a mixture of novel carboxy-terminal peptides, terminated by in-frame STOP codons. To date, apoB-27.6 is the smallest truncated species identified in plasma and associated with lipid. An explanation for this could be the hydrophobic nature of the novel carboxy-terminal peptides, which might enable stabilization of the particles by solubilization of sufficient lipid.