What is the role of familial ligand defective apoB-100 in the etiology of familial hypercholesterolemia (FH)?

Updated: Oct 04, 2021
  • Author: Mose July, MD, CCD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Answer

Familial ligand defective apoB-100 (FLDB), also called familial defective apoB-100, is responsible for a syndrome almost indistinguishable from heterozygous FH. Instead of an abnormal or absent LDL receptor, this syndrome is caused by an abnormality at the binding site of apoB-100, which impedes its role as a ligand for the receptor. ApoB-100 is a single polypeptide chain composed of 4536 amino acids. The gene resides on the short arm of chromosome 2 and the first described mutation was a substitution of glycine for arginine at the codon for amino acid 3500. Different mutations at the same and different codons have since been described.

Although the LDL receptors are normal in both number and function, LDL is taken up inefficiently, leading to elevated LDLc levels that can be indistinguishable from those associated with heterozygous FH. These patients can present with cutaneous manifestations and an increased risk of premature CAD similar to patients with heterozygous FH. Because LDL receptors function normally with respect to the apoE ligand, uptake of very low-density lipoprotein, very low-density lipoprotein remnants, and intermediate-density lipoprotein is normal. The consequence may be that patients with defective apoB-100 may have a clinically more benign course than patients with heterozygous FH. The finding that patients homozygous for familial defective apoB-100 are clinically similar to those with the heterozygous condition supports this supposition.


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