Missense mutation Q384K in the APOB gene affecting the large lipid transfer module of apoB reduces the secretion of apoB-100 in the liver without reducing the secretion of apoB-48 in the intestine

Background: Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein.

Objective: To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.1 mmol/l.

Methods: DNA sequencing of the translated exons with flanking intron sequences of the genes adenosine triphosphate-binding cassette transporter 1, angiopoietin-like protein 3, apolipoprotein B, apolipoprotein A1, lecithin-cholesterol acyltransferase, microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9.

Results: The patient was homozygous for mutation Q384K (c.1150C>A) in the apolipoprotein B gene, and this mutation segregated with hypobetalipoproteinemia in the family. Residue Gln₃₈₄ is located in the large lipid transfer module of apoB that has been suggested to be important for lipidation of apolipoprotein B through interaction with microsomal triglyceride transfer protein. Based on measurements of serum levels of triglycerides and apolipoprotein B-48 after an oral fat load, we conclude that the patient was able to synthesize apolipoprotein B-48 in the intestine in a seemingly normal fashion.

Conclusion: Our data indicate that mutation Q384K severely reduces the secretion of apolipoprotein B-100 in the liver without reducing the secretion of apolipoprotein B-48 in the intestine. Possible mechanisms for the different effects of this and other missense mutations affecting the large lipid transfer module on the two forms of apoB are discussed.