APOLIPOPROTEIN B (ApoB) DEFICIENCY

In addition to familial hypercholesterolemia (FH), which is mainly caused by causal variants in the LDL receptor gene, there is another autosomal dominantly inherited form of hypercholesterolemia caused by pathogenic variants in the APOB gene (prevalence approx. 1:700–1,000). The gene product, apolipoprotein B, is a component of LDL particles and serves as a ligand in the receptor-mediated uptake of LDL into the cell. This disorder of LDL metabolism, known as familial apolipoprotein B deficiency (familial ligand defective Apo B, FLDB), is associated with a lower degree of hypercholesterolemia than FH, but patients still have a significantly increased coronary risk.

The prevalence of the most common variant in the APOB gene, c.10580G>A, or p.(Arg3527Gln) (historically R3500Q), is reported to be 1:450 in the normal population, which roughly corresponds to the frequency of heterozygous LDL receptor defects. Even in heterozygotes, a reduced affinity of ApoB for the LDL receptor leads to an increase in total cholesterol of 70-95 mg/dl compared to control subjects. Another pathogenic variant, c.10579C>T, which leads to a different amino acid substitution [p.(Arg3527Trp)] in the same codon, has been identified as the cause of FH, particularly in Asian populations. Variants at amino acid position 3527 are detected in approximately 1-5% of patients with familial hypercholesterolemia. Homozygosity for an FLDB is extremely rare; the phenotype resembles that of heterozygous FH.

Based on recent data, molecular genetic testing for nucleotide position c.10672C>T [p.(Arg3558Cys)] (historically R3531C) is no longer offered. Contradictory statements have been made regarding the segregation and functional effect of this variant, meaning that it must be classified as a variant of unclear significance in accordance with the guidelines for variant classification.

References

Youngbloom et al. 2016, GeneReviews® [Internet] / Olfson et al. 205, PLoS One 10:e0135193 / Burnett et al. 2012, Eur J Hum Genet 20 / Futema et al. 2012, J Med Genet 49:644 / Ng et al. 2010, Curr Opin Lipidol. 21:141 / Benn et al. 2005, J Biol Chem. 280:21052