Mutations and variants of apolipoprotein B that affect plasma cholesterol levels

Apolipoprotein (apo-) B100 is the exclusive apolipoprotein of low density lipoproteins (LDL0, which transport most of the plasma cholesterol in humans. Mutations in apo-B100 can cause either hypocholesterolemia or hypercholesterolemia. Familial hypobetalipoproteinemia, which leads to hypocholesterolemia, has been shown to be caused by defects in the apo-B gene that terminate translation prematurely and result in the production of truncated proteins. The mutations responsible for the hypocholesterolemia have been either single nucleotide substitutions or deletions. Familial defective apo-B100, which leads to hypercholesterolemia, is caused by a point mutation in the receptor-binding domain of apo-B100. The mutation disrupts the binding of LDL to the LDL receptor, thereby disrupting LDL receptor-mediated catabolism and resulting in hypercholesterolemia. A variant form of apo-B, apo-B48, is also critical for lipoprotein metabolism. Apolipoprotein B48 is obligatory for the secretion of chylomicrons. It is formed from an RNA-edited apo-B mRNA in which codon 2153 has been converted from a CAA (glutamine) codon to a premature UAA (stop) codon. The first cytosine in this codon is deaminated to form uracil. The minimum nucleotide recognition sequence for the editing mechanism has been reported to be between 26 and more than 63 nucleotides surrounding codon 2153. The apo-B mRNA editing mechanism, which appears to be a cytosine deaminase, and its regulation are being actively investigated.