Identification of a Novel apoB Variant in a Family Exhibiting Hypocholesterolemia: Mechanistic Insights

Familial hypobetalipoproteinemia (FHBL) is a rare autosomal codominant disorder. FHBL is often caused by a defect in apoB production that is required for lipoprotein formation. Here we identified three family members that exhibited very low circulating cholesterol levels. Analyses of their plasma lipid profiles revealed that the affected individuals have low levels of cholesterol and LDL-cholesterol (LDLc) lipoproteins, with no difference in lipoprotein particle size. Sequencing of the APOB gene revealed a single heterozygote deletion of an adenosine in exon 3 at the nucleotide position 1268 in all affected members. This deletion introduces a reading frame shift at glutamine 380 resulting in a stop codon at position 397. This C-terminally truncated apoB, called apoB9, is a variant spanning ~9% of the full-length protein. Upon expression of apoB9 in human hepatocyte IHH cells, the protein was detected intracellularly but it did not exit the endoplasmic reticulum and hence was not secreted into the media. Molecular modeling revealed that apoB9 lacks the βA- and βB-sheets that are required for lipid particle formation, which can explain the absence of apoB9 secretion and the low levels of plasma apoB in the affected family members, likely modifying their risk of developing CVD.