Familial defective apolipoprotein B-100. Comparison with familial hypercholesterolemia in 18 cases detected in Munich.

Abstract

It has recently been suggested that a substitution of glutamlne for arginlne at residue 3500 of apolipoprotein (apo) B-100 causes familial defective apo B-100 (FDB), an autosomal, dominantly Inherited disorder, which leads to Increased serum cholesterol levels. From a sample of 243 patients from Munich with type Ma hyperllpoprotelnemia (HL), we have Identified eight individuals with the apo B-100 arglnlne ( j 600) -»glutamine mutation. In a group of 57 subjects with defective low density llpoproteln receptor (LOLR), no mutant apo B alleles were detected. The frequency of FDB In patients with type Ha HL was estimated to be 3%. In the kindreds of three of the probands, 10 additional carriers of the apo B mutation were Identified. Clinical and biochemical data reveal a striking similarity between patients with FDB and those with a defect in the LDLR gene. Our data support previous findings that FDB Is a serious disorder causing premature atherosclerosis.

Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene.

“…Key Words • familial hypercholesterolemia • receptor • HMG CoA reductase inhibitors LDL not bind normally to LDL; class 4 defects produce a protein that fails to internalize LDL particles; and class 5 defects encode receptors that are not recycled to the cell surface in a normal fashion. 3 - 4 A defect in the ligand for the LDL receptor, apolipoprotein (apo) B, is phenotypically indistinguishable from FH 5 - 6 and is seen in approximately 1/500 subjects. In the province of Quebec, Canada, the prevalence of FH is approximately 1/270, with geographical clusters having a frequency as high as 1/80.…”

Cellular processing of apolipoprotein B‐containing lipoproteins from young post‐infarction patients and healthy controls

“…Different expression of apo B on the LDL particle surface [30] and/or steric effects of the LDL particle influencing the interaction with the LDL receptor [3 11 could be possible explanations for differences in binding affinity between LDL subclasses. Another but less likely explanation would be the presence of familial defective apolipoprotein B-100 [32] among occasional patients, a condition which is unusual in hypertriglyceridaemic patients [33] and in young post-infarction patients [34].…”

A Case Report of a South Asian Family with Homozygous and Heterozygous Familial Defective APOB-100 Caused by p.(Arg3527Trp)

“…The clinical and lipid phenotype of FDB patients overlap with those carrying an LDLR mutation, but on average they have a milder presentation than FH due to LDLR mutations [4,5] and in heterozygous FDB, serum cholesterol varies between 7.5 -9.0 mmol/l. Similarly, in the few cases reported of homozygous FDB, serum cholesterol level seen are between 10-16 mmol/l [6,7] and the severity of the disease is more comparable to heterozygous familial hypercholesterolemia caused by LDLR mutations [8][9][10].…”

“…The clinical and lipid phenotype of FDB patients overlap with those carrying an LDLR mutation, but on average they have a milder presentation than FH due to LDLR mutations [4,5] and in heterozygous FDB, serum cholesterol varies between 7.5 -9.0 mmol/l. Similarly, in the few cases reported of homozygous FDB, serum cholesterol level seen are between 10-16 mmol/l [6,7] and the severity of the disease is more comparable to heterozygous familial hypercholesterolemia caused by LDLR mutations [8][9][10].The most common mutation causing FDB alters the Arginine at position 3527 to Glutamine (p.(Arg3527Gln)) [11][12][13][14][15][16], with the LDL containing APOB-Gln showing very low affinity for the LDL-receptor in in vitro assays [16,17] and reduced clearance from the blood in turnover studies (18). The frequency of this mutation in (non-Finish) European populations reported in the ExAC database is 0.034% (http://exac.…”