Apolipoprotein B gene mutations affecting cholesterol levels

Abstract

In the past 5 years, many different mutations in the apolipoprotein (apo) B gene have been described that affect plasma cholesterol levels. More than 20 different mutations in the apoB gene have been shown to cause familial hypobetalipoproteinaemia, a condition characterized by abnormally low plasma concentrations of apoB and LDL cholesterol. Almost all of the mutations are nonsense or frameshift mutations that interfere with the translation of a full-length apoB100 molecule. Many, but not all, of these apoB gene mutations result in the synthesis of a truncated species of apoB that can be detected within the plasma lipoproteins. Familial hypobetalipoproteinaemia heterozygotes are almost always asymptomatic and have LDL cholesterol levels about one-quarter to one-third of those of unaffected family members. Several homozygotes and compound heterozygotes for familial hypobetalipoproteinaemia have been described. In these individuals, the LDL cholesterol levels are extremely low, usually less than 5 or 10 mg dl-1, and the clinical phenotype is variable, ranging from completely asymptomatic to severe problems related to intestinal fat malabsorption. One missense mutation in the apoB gene (an Arg----Gln substitution at apoB amino acid 3500) is associated with very poor binding of apoB100 to the cellular LDL receptor. This syndrome has been designated familial defective apolipoprotein B (FDB). The amino-acid substitution at residue 3500 delays the clearance of LDL from the plasma and results in hypercholesterolaemia. In some Western populations, the frequency of FDB heterozygotes appears to be as high as 1 in 500 individuals.

Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice.

“…Thus, increased ca- tabolism of HDL (and apoAI) may be responsible for the reductions in HDL cholesterol and apoAI. In human HBL homozygotes, HDL concentrations have been variable, ranging from low to elevated (7)(8)(9)(10).…”

“…Humans homozygous for "null alleles" have a complete absence of apoB-containing lipoproteins and can be severely affected with symptoms of intestinal fat malabsorption, fat-soluble vitamin deficiency, and neurological problems. The phenotypes of individuals homozygous for mutant APOB alleles leading to the synthesis of truncated apoB proteins are variable (7)(8)(9)(10). Heterozygotes have onethird to one-half of normal apoB and LDL-cholesterol levels and are almost always asymptomatic.…”

Hammerhead Ribozyme Cleavage of Apolipoprotein B mRNA Generates a Truncated Protein

“…Moreover, they appear to be protected from atherosclerotic disease (6). Familial hypobetalipoproteinemia is characterized by the presence of truncated apoB produced by one of the alleles, and the levels of truncated apoB are barely detectable (7). In most cases, the underlying mechanism for the reduced apoB concentration is unclear; it could be the result of an inability of the truncated apoB variants to assemble and be secreted as normal triglyceride-rich lipoprotein.…”

Factors affecting the regulation of apo b secretion by liver cells

“…in Farese et al(103). References given in iralics are from Farese et al(103); references in standard type are listed in the References at the end of this review.…”

“…in Farese et al(103). References given in iralics are from Farese et al(103); references in standard type are listed in the References at the end of this review. increase in apo B secretion.Cianflone et al (123) found that oleic acid addition increased the number of apo B particles secreted, but not the size.…”