Although there are many genetic polymorphisms in the APOB gene, it is not known whether or not they are harmful. Only the familial faulty apoB100 mutation in APOB p.(Arg3527Gln) indisputably causes familial hypercholesterolemia (FH). The HF in three unrelated Spanish families caused by a novel APOB mutation is described. Its pathophysiology has been established using family segregation and apoB-LDL receptor binding studies.

The three probands represent two women and one man who were sent to evaluate their hypercholesterolemia at the Lipid Unit of the Miguel Servet Hospital in Zaragoza, Spain. In addition, family history revealed a predominance of hypercholesterolemia in their families, ruling out secondary causes. The table provides an overview of their clinical features.

The c.10030A>G; p.(Lys3344Glu) variation was discovered by sequencing investigation of the LDLR, APOB, PCSK9, and APOE genes. No more harmful mutations were discovered. In the family study, there were 14 first-degree relatives, 8 of whom had the APOB variation and had a mean age of 42.5 years. In carriers and 147 (98-179) in unaffected relatives, LDLc had a mean (range) of 309 mg/dL (254-419). A decrease equal to that achieved with apoB p.(Arg3527Gln) and around 50% lower than that obtained in control sera was seen in the apoB-LDL receptor binding analysis of the serum of the three probands (EC50).

The p.(Lys3344Glu) variation of APOB is responsible for FH, and its mechanism is a flaw in the protein’s affinity for the LDL receptor.