Journal of Clinical Lipidology · Feb 20, 2026

Identification of a novel apoB variant in a family exhibiting hypocholesterolemia: Mechanistic insights

By Essalamani R, Evagelidis A, Roubtsova A et al.

BACKGROUND: Familial hypobetalipoproteinemia is a rare autosomal codominant disorder, often caused by a defect in apolipoprotein B (apoB) production required for lipoprotein formation and secretion. OBJECTIVE: Characterization of the lipid profiles of 3 family members exhibiting very low circulating cholesterol levels. METHODS: Plasma samples from the control sibling and the affected patients were analyzed. Fast protein liquid chromatography and high-performance liquid chromatography were used to characterize the lipid profiles, size, and distribution of lipoprotein particles. Exome sequencing of family members revealed a single-nucleotide deletion in APOB in the 3 affected individuals. The effect of the single-nucleotide deletion on the secretion of apoB was analyzed in immortalized human hepatocyte (IHH) cells. RESULTS: Plasma lipid profiles revealed that the affected individuals have low levels of total cholesterol and low-density lipoprotein cholesterol, with no difference in lipoprotein particle size. DNA sequencing of APOB 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. The C-terminally truncated apoB, called apoB9, is a variant spanning ∼9% of the full-length protein. Upon expression of apoB9 in IHH cells, the protein did not exit the endoplasmic reticulum/cis-Golgi 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. CONCLUSION: Our data suggested that the affected family members have ∼50% to 60% lower apoB levels and are likely protected against the development of atherosclerosis and cardiovascular diseases.

doi.org/10.1016/j.jacl.2026.02.013Open access, accepted manuscriptPubMed 41807234Mechanisms