Familial Defective Apolipoprotein B-100 Research Articles

Sib-pair analysis detects elevated Lp(a) levels and large variation of Lp(a) concentration in subjects with familial defective ApoB.

Whether or not Lp(a) plasma levels are affected by the apoB R3500Q mutation, which causes Familial Defective apoB (FDB), is still a matter of debate. We have analyzed 300 family members of 13 unrelated Dutch index patients for the apoB mutation and the apolipoprotein(a) [apo(a)] genotype. Total cholesterol, LDL-cholesterol, and lipoprotein(a) [Lp(a)] concentrations were determined in 85 FDB heterozygotes and 106 non-FDB relatives. Mean LDL levels were significantly elevated in FDB subjects compared to non-FDB relatives (P < 0.001). Median Lp(a) levels were not different between FDB subjects and their non-FDB relatives. In contrast, sib-pair analysis demonstrated a significant effect of the FDB status on Lp(a) levels. In sib pairs identical by descent for apo(a) alleles but discordant for the FDB mutation (n = 11) each sib with FDB had a higher Lp(a) level than the corresponding non-FDB sib. Further, all possible sib pairs (n = 105) were grouped into three categories according to the absence/presence of the apoB R3500Q mutation in one or both subjects of a sib pair. The variability of differences in Lp(a) levels within the sib pairs increased with the number (0, 1, and 2) of FDB subjects present in the sib pair. This suggests that the FDB status increases Lp(a) level and variability, and that apoB may be a variability gene for Lp(a) levels in plasma.

Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European countries.

A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B- 100 (FDB). In 205 FDB patients from Germany (n = 73). The Netherlands (n = 87), and Denmark (n = 45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene (SfaNI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women (SfaNI: P = .04 and .03 for TC and LDL-C, respectively; Nco I; P = .003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S + A + N + allele had 13% to 20% higher TC than non-S + A + N + subjects (P = .02 [TC, men]; P = .01 [LDL-C, men]; P = .005 [TC, women]; and P = .004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e3e2, e3e3, and e3e4) with cholesterol concentrations was seen in S + A + N + but not in non-S + A + N + subjects and in P-P- but not in P + P + or P + P- subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.

Statin therapy in a kindred with both apolipoprotein B and low density lipoprotein receptor gene defects

We studied an extended family of similar genetic and environmental background to determine whether there is a difference in response to statin therapy in those subjects with heterozygous familial hypercholesterolaemia (FH Afrikaner-1 (FH1) or FH Afrikaner-2 (FH2)) compared to those with familial defective apo B-100 (FDB), or both FH plus FDB. Fasting lipid profiles and Lp(a) levels were done on 18 members of the family and then repeated following 6 weeks of therapy with simvastatin 20 mg daily. Statin therapy reduced LDL-cholesterol (LDL-C) by 31% in those with FH ( n=7); 29.8% in FDB ( n=5) and 25.4% in those with both FDB and FH ( n=5). There was no response to statin therapy in the single subject with both FH1, FH2, as well as FDB. Lp(a) levels did not change significantly either within or between any of the groups following statin therapy (FH from 6.5 (1.2–72.3) to 5.3 (1.2–52.3), FDB from 6.1 (4.70–71) to 8.2 (5.7–79) and FDB plus FH from 4.5 (2.6–17.4) to 3.1 (1.9–24) mg/dl). Statins are equally effective in lowering LDL-C in related subjects with heterozygous FH, FDB or both FDB plus FH. The ability of statins to lower LDL-C in FDB is probably due to increased hepatic uptake of lipoprotein precursors of LDL that can bind via apo E receptors. Lp(a) concentration is not reduced by drugs that stimulate LDL receptor activity implying that LDL receptors do not contribute greatly to normal clearance of Lp(a) in hypercholesterolaemic subjects with defects in receptor-mediated endocytosis of LDL.

Screening of the 3′ two-thirds of the coding area of the apo B gene in Finnish hypercholesterolemic patients: Report of six new genetic variants

Hypercholesterolemia clustering in families not explained by either low density lipoprotein (LDL)-receptor mutations producing familial hypercholesterolemia (FH), or the apolipoprotein B (apo B) Arg3500→Gln mutation with familial defective apo B (FDB), is common in the Finnish population. In search of previously unknown apo B mutations, we screened exons 26 to 29 of the apo B gene in 68 Finnish severely hypercholesterolemic (≥8 mmol/l) non-FH, non-FDB patients, using a single-strand conformation polymorphism analysis based screening method. Four rare and two polymorphic previously unreported DNA variations were detected. The rare variants were a three-nucleotide deletion, with the deletion of Asp2186, an A11961→G change leading to a Thr3918→Ala change, a T12922→G change causing a Val4238→Ala substitution, and a neutral T12935→C change leading to a new RsaI cutting site. The polymorphic G12937→C and G13569→A changes leading to Arg4243→Thr and Ala4454→Thr substitutions, respectively, had minor allele frequencies of 0.03 and 0.02. None of these variants seemed to explain the hyperlipidemia in these patients. A major Finnish mutation causing severe hypercholesterolemia is unlikely to exist in the 3′ two-thirds of the coding area of the apo B gene.

Analysis of novel apolipoprotein B mutations using a modified U937 cell line LDL binding assay

The U937 myelomonocyte proliferation assay can be used to detect patients with familial defective apolipoprotein B-100 (FDB). Previous studies have employed electronic cell counting to assess cell proliferation. We simplified the assay using 3H-thymidine incorporation DNA analysis to measure cell growth. We tested the modified method by analyzing the effects of different concentrations of native low density lipoproteins (LDL), methylated LDL, as well as LDLs obtained from patients with FDB on cell growth. Methylation of LDL to various degrees reduced cell proliferation correspondingly, and LDLs obtained from FDB patients decreased cell growth confirming that the modified method was able to detect binding defective species of LDL. We applied this method to analyze three novel apoB polymorphisms recently characterized in this laboratory (apoB His1896→Arg, apoB Asn1887 → Ser, apoB Ala4454 → Thr, which did not significantly alter U937 cell proliferation. Our results show that this simplified assay can be used for screening for LDL variants with defective binding.

Increased clearance of low density lipoprotein precursors in patients with heterozygous familial defective apolipoprotein B-100: a stable isotope approach

In familial defective apolipoprotein B-100 (FDB) the presence of a mutant apolipoprotein (apo) B-100 (FDB3500Q/W) in LDL markedly reduces their affinity for the LDL receptor, leading to elevated LDL cholesterol levels. However, the hypercholesterolemia in most FDB patients is relatively mild when compared with, e.g., familial hypercholesterolemia (FH). In order to study mechanisms that may partly alleviate the clinical consequences of FDB, we investigated the in vivo kinetics of apoB-100-containing lipoproteins in five FDB heterozygotes (total cholesterol: 7.84 +/- 1.37 mmol/I; total apoB: 1.68 +/- 0.37 g/l; mean +/- SD) and six normolipidemic controls (4.61 +/- 0.62 mmol/l; 0.98 +/- 0.12 g/l) using a stable isotope approach. During and after a 10-12 h primed, constant infusion of either [13C6]phenylalanine or [2H3]leucine, tracer enrichment was determined in apoB-100 from ultracentrifugally isolated VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), IDL (Sf 12-20), LDL1 (Sf 7-12), and LDL2 (Sf 0-7). The rates of apoB-100 production, catabolism, and transfer were estimated by model-based compartmental analysis. The overall fractional catabolic rate (FCR) of IDL apoB-100 in FDB was substantially increased (2.99 +/- 0.68 pools/day vs. 1.70 +/- 0.23 pools/day in controls, P < 0.01). The fractional rate of apoB-100 transfer from IDL to LDL in FDB was decreased (0.97 +/- 0.13 pools/day vs. 1.24 +/- 0.10 pools/day, P < 0.05). The FCR of LDL apoB-100 in FDB was decreased (0.18 +/- 0.07 pools/day vs. 0.56 +/- 0.05 pools/, P < 0.01). Finally, the input rate of LDL apoB-100 in FDB was markedly decreased (9.45 +/- 2.96 mg/kg day1 vs. 15.54 +/- 1.70 mg/kg day1, P < 0.05). Our data suggest that the relatively small increase of LDL concentrations in FDB is due to an increased clearance of LDL precursor particles via the LDL-receptor and apoE-receptors as well as a decreased conversion of IDL to LDL - two mechanisms that distinguish FDB from FH.

Familial defective apolipoprotein B-100: a study of patients from lipid clinics in Scotland and Wales.

Familial defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder, which may be associated with hypercholesterolaemia. The defect is caused by the substitution of glutamine for arginine at amino acid residue 3500 of apo B-100. A total of 357 hypercholesterolaemic patients, 48 with a clinical diagnosis of familial hypercholesterolaemia attending lipid clinics in Scotland and Wales, were screened for the presence of FDB. Seven unrelated individuals, five of whom had a family history of coronary heart disease, and a further 11 first-degree relatives, were shown to be heterozygous for the mutation. Pedigree analysis demonstrated the mutation to be present on a single haplotype, suggesting that in Britain it is inherited from a common ancestor. Treatment of 11 heterozygous individuals with lipid-lowering medication showed falls in total and low density lipoprotein cholesterol ranging from 11.6 to 38.8% and 5.3 to 49.5%, respectively. In view of the condition's association with coronary heart disease and hypercholester-olaemia, it may be worthwhile identifying carriers attending lipid clinics, so that affected siblings can be offered cholesterol-lowering treatment where necessary.

Screening and identification of familial defective apolipoprotein B-100 in clinical samples by capillary gel electrophoresis

Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder. It is characterized by a decreased affinity of low density lipoprotein (LDL) for the LDL receptor, as a consequence of a substitution of adenine by guanine in exon 26 of the apolipoprotein B-100 gene, coding for the putative LDL receptor-binding domain of the mature protein. This disorder is associated with a strikingly high incidence of arteriosclerosis and tends to cause disease and premature death. In this communication we describe a rapid capillary gel electrophoretic method in combination with molecular biology techniques to facilitate the diagnosis of FDB. Mutation screening for FDB is performed by an allele-specific amplification followed by capillary gel electrophoresis (CGE). For the combined polymerase chain reaction (PCR)-CGE method, a total analysis time of only 3 h is needed, a period that is normally necessary for the run and for staining of the gel only, not including the time for PCR, gel casting, etc. In our pilot study 4 of 43 hypercholesterolemic patients were found to have the predominant apoB 3500 codon mutation. The verification is demonstrated by DNA-sequencing. This pilot study will be followed by a large cohort analysis of the south-west German population to determine the frequency of FDB in this area. The PCR-CGE method on the Dionex capillary electrophoresis system (CES I) allows rapid, fully automated detection of the mutation resulting in the unequivocal diagnosis of FDB.

Familial defective apolipoprotein B-100 (FDB): effect of simvastatin therapy on LDL-receptor binding

Heterozygotes for familial defective apolipoprotein B-100 (FDB) have two populations of low density lipoprotein (LDL), one bearing normal apolipoprotein B-100 (apo B) and the other bearing defective apo B which exhibits a much lower affinity for the LDL-receptor. If HMGCoA reductase inhibitors such as simvastatin lowered LDL mainly by up-regulating LDL-receptor mediated clearance, they should decrease the overall binding affinity of LDL from an FDB heterozygote by selectively decreasing LDL bearing normal apo B. We compared how LDL from FDB heterozygotes competed with normal 125I-labelled LDL for binding to LDL-receptors while on and off therapy with simvastatin. The LDL of FDB heterozygotes had 40% ( n = 10) the affinity of normal LDL ( n = 12) for the LDL receptor on cultured fibroblasts, and 55% ( n = 6) of normal LDL ( n = 6) for that on HepG2 cells. Treatment of FDB subjects with simvastatin ( n = 10) decreased serum LDL by 22% but had no effect on its binding affinity for LDL receptors on either cell. We conclude that, in FDB heterozygotes, simvastatin lowers LDL without changing its affinity for LDL-receptors, indicative of lowering of LDL containing both normal and defective apo B. This is consistent with the major LDL lowering effect being associated with decreased synthesis of LDL, rather than enhanced LDL-receptor clearance.

Seven DNA polymorphisms in the LDL receptor gene: application to the study of familial hypercholesterolemia in Spain.

We have performed restriction fragment length polymorphism (RFLP) analysis at the low density lipoprotein receptor (LDLR) locus in order to investigate the molecular genetics of familial hypercholesterolemia (FH) in Spain. Firstly, a sample of 50 unrelated patients with a clinical diagnosis of FH was screened for the presence of major rearrangements at this locus by Southern blot analysis of BglII digested genomic DNA. Four different mutations were detected, accounting for 8% of the mutant alleles in the Spanish FH sample. Then, we determined the relative allele frequency and estimated linkage disequilibrium between seven RFLPs of the LDLR gene in the remaining 46 FH patients and in 61 normolipidemic controls. HincII, AvaII, PvuII, MspI, and NcoI are the most polymorphic sites with individual PIC values higher than 0.28, whereas the TaqI and StuI sites display low levels of polymorphism. The usefulness of the seven RFLPs to confirm a clinical diagnosis of FH was investigated in 15 FH-families, consisting of 118 individuals, in whom the presence of Familial Defective Apolipoprotein B-100 (FDB) due to the apoB3500 mutation was excluded. Independent haplotypes were constructed for 71 chromosomes: 15 FH and 56 control haplotypes. A total of 14 different haplotypes was found. In 12 families, clinical diagnosis of FH was confirmed by cosegregation analysis, which makes these RFLPs useful for studying the inheritance of the LDLR gene in 80% of Spanish families with FH. Comparison of haplotypes found in the Spanish sample with those found in Swiss and Norwegians suggests heterogeneity of haplotypes among European populations.

New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug.

Niacin has been used for many years to treat hyperlipidemia. It has been shown to reduce coronary death and non-fatal myocardial infarction and, in a separate analysis of long-term (15-year) follow-up, all cause mortality. It reduces total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides and increases high density lipoprotein cholesterol (HDL-C). Sustained-release niacin may be associated with more dramatic changes in LDL-C and triglyceride, whereas the short acting preparation causes greater increases in HDL-C. The increase of HDL-C occurs at a lower dose (1500 mg/day) than the reduction of LDL-C (> 1500 mg/day). Niacin also favorably influences other lipid parameters including lipoprotein(a) [Lp(a)], alimentary lipemia, familial defective apolipoprotein B-100 and small dense LDL. Combination of niacin with a bile acid sequestrant or a reductase inhibitor represents a powerful lipid-altering regimen. Whereas the reductase inhibitors and bile acid binding resins primarily affect LDL-C, the combined therapy has a synergistic effect to reduce LDL-C and, in addition, the niacin reduces triglycerides and increases HDL-C. The major drawback in the use of niacin is associated side effects (flushing and palpitations) and toxicity (worsening of diabetes control, exacerbation of peptic ulcer disease, gout, hepatitis). Niacin has a long history of use as a lipid lowering agent and has several attractive features. Unfortunately, the side effect profile of this agent warrants its use only in patients with marked dyslipidemia in whom side effects and potential toxicity are closely monitored.

Phenotypic expression in double heterozygotes for familial hypercholesterolemia and familial defective apolipoprotein B-100

Variability in the expression of monogenic lipid disorders may be observed in patients carrying the same DNA mutation, suggesting possible genetic or environmental interactions. Our objective was to investigate the genotype-phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholesterolemia. In probands, segregation analysis complemented by DNA sequencing identified heterozygous defective alleles and mutations on two nonallelic loci for two monogenic lipid disorders: familial hypercholesterolemia at the low density lipoprotein (LDL) receptor locus and familial defective apolipoprotein B-100 at the locus encoding its ligand, apolipoprotein B-100. The LDL-receptor missense mutations had been reported in French Canadians. The apolipoprotein B mutation was the Arg3500Gln founder mutation in Northern Europe. Probands had an unusual phenotype of aggravated hypercholesterolemia that was complicated with premature coronary arterial disease, although remaining responsive to lipid-lowering drugs. This phenotype was distinct from that observed in their heterozygous relatives and distinct from those observed in FH or FDB homozygotes. These cases refer to a new class of patients with digenic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the observed phenotype of aggravated hypercholesterolemia gives further evidence that receptor and ligand play distinct roles in regulating LDL metabolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hypercholesterolemia.

Clinically applicable mutation screening in familial hypercholesterolemia.

Mutations in the LDL receptor (LDLR) gene and the codon 3500 region of the apolipoprotein (apo) B-100 gene result in the clinically indistinguishable phenotypes designated familial hypercholesterolemia (FH) and familial defective apo B-100 (FDB), respectively. Introduction of genetic diagnosis in phenotypic FH families may remove the diagnostic inaccuracies known from traditional clinical/biochemical FH diagnosis and allow more differentiated prognostic evaluations and genetic counseling of FH/FDB families. Previous genetic screening methods for FH have, however, been too cumbersome for routine use, however. To overcome these problems, we designed a mutation screening assay based on the highly sensitive denaturing gradient gel electrophoresis (DGGE) technique. The setup allows within 24 hr to pinpoint if and where a potential mutation is located in the LDLR promoter, the 18 LDLR gene exons and corresponding intronic splice site sequences, or in the codon 3500 region of apo B-100. The pinpointed region is subsequently sequenced. As an evaluation of the sensitivity, we demonstrated the ability of the assay to detect 27 different mutations or polymorphisms covering all the examined regions, except LDLR exon 16. In conclusion, a simple, but sensitive, clinically applicable mutation screening assay based on the DGGE principle may reveal the underlying mutation in most FH/FDB families and offer a tool for a more differentiated prognostic and therapeutic evaluation in FH/FDB.

Does the presence of the 3500 mutant apolipoprotein B-100 in low density lipoprotein particles affect their atherogenicity?

Apolipoprotein B-100 (apo B-100) is the protein component of low density lipoprotein (LDL) responsible for its binding and clearance by LDL receptors (LDL-R). In familial defective apo B-100 (FDB), a mutation in apo B-100 at residue 3500 markedly reduces its affinity for LDL-R, often causing accumulation of defective LDL particles, and an increased proneness to coronary artery disease (CAD). In FDB heterozygotes, about 70% of the LDL particles are mutant, which may alter their atherogenicity relative to LDL containing normal apo B. Therefore, we compared CAD in heterozygous FDB with CAD in heterozygous familial hypercholesterolemia (FH), since raised LDL is usually present from birth in both conditions, and in FH the LDL particles that accumulate have normal apo B, as the inherited defect involves the LDL-R. The clinical presentation of coronary atherosclerosis and its angiographic appearance were examined in FDB and FH patients matched for conventional cardiac risk factors (hypertension, smoking, sex) and serum lipid levels. There was no significant difference between the FDB and FH patients ( n = 11 pairs) in the type of cardiac symptoms or their ages of onset (50 ± 9 vs. 45 ± 11 years). Coronary angiographic appearance was also similar in both groups ( n = 9 pairs). These observations suggest that LDL particles with the 3500 mutation in apo B have the same atherogenicity as LDL particles with normal apo B.

Differences in the Phenotypic Characteristics of Subjects With Familial Defective Apolipoprotein B-100 and Familial Hypercholesterolemia

Familial defective apolipoprotein B-100 (FDB) is a recently identified autosomal-dominantly inherited disorder caused by a point mutation in the apolipoprotein (apo) B gene. To determine whether the phenotypic characteristics in FDB subjects are similar to those in subjects with familial hypercholesterolemia (FH), 76 kindreds fulfilling the clinical criteria for heterozygous FH/FDB were characterized using molecular biological techniques. Allele-specific polymerase chain reaction (PCR) at the apoB locus was used for diagnosis or exclusion of FDB. PCR-based methods for detection of two point mutations (V408M and P664L) at the LDL receptor (LDLR) locus, cosegregation analysis using eight restriction fragment length polymorphisms (RFLPs) at the LDLR locus, or the exclusion of FDB confirmed the clinical diagnosis of FH. Three kindreds were not included because of a missing cosegregation between a particular haplotype and the FH phenotype. We predicted that a similar number of kindreds would be detected in the two groups, assuming comparable prevalences of the diseases in our population and similar phenotypic characteristics. However, only nine kindreds were identified with the FDB mutation compared with 64 kindreds with FH (P < .0001). From these 73 kindreds, 28 FDB heterozygotes and 129 FH heterozygotes were compared using multivariate analysis. There were no differences between these two groups with respect to age, sex, and apoE genotype distribution, lipoprotein(a) concentrations, body mass index, blood pressure, and smoking habits. However, FDB subjects demonstrated significantly lower concentrations of total cholesterol (8.1 versus 10.2 mmol/L, P < .001), LDL cholesterol (6.3 versus 8.2 mmol/L, P < .001), and triglycerides (1.3 versus 1.8 mmol/L, P = .025) and higher concentrations of HDL cholesterol (1.4 versus 1.2 mmol/L, P = .015) than subjects with FH. In contrast to FH, female FDB subjects tended to have higher concentrations of total cholesterol (8.9 versus 7.5 mmol/L, P = .032) and LDL cholesterol (7.1 versus 5.7 mmol/L, P = .026) than FDB males. The same results regarding total and LDL cholesterol and sex differences were observed when individual data of 238 FDB and 415 FH subjects from the literature were compared. In addition, FDB subjects showed much larger total cholesterol fluctuations than FH subjects (median of intraindividual coefficients of variation: FDB, 14.5%; FH, 5.3%; P < .001). In summary, these results demonstrate that FDB subjects tend to have a milder form of hyperlipoproteinemia than FH subjects and that only a part of the subjects with FDB fulfill the established criteria for identifying FH.

Hyperlipidaemia associated with genetic variation in the apolipoprotein B gene.

Common variants at the apolipoprotein B gene locus are associated with hyperlipidaemia, but conflicting data have been presented in the literature concerning the size of the effects and which polymorphisms give the best signal in the different groups of individuals studied. In this review, we will present a critique on the use and interpretation of association studies, with respect to the recent apolipoprotein B DNA polymorphism studies. The impact of these common polymorphisms and rare mutations of apolipoprotein B, primarily the substitution of arginine by glutamine at residue 3500 (R3500Q) that causes familial defective apolipoprotein B100, will also be considered.

Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia.

The apoB arginine-to glutamine change at codon 3500 has become established as a cause of failure of binding of the LDL particle to its receptor and the consequent hypercholesterolemia of familial defective apoB 100. A search for further similar mutations was undertaken by systematic screening of a candidate region of the apoB gene from individuals with hypercholesterolemia. Polymerase chain reaction and denaturing gradient gel electrophoresis were used. We describe two families in which a different mutation in the codon 3500 causes an arginine-to-tryptophan substitution. Most adults in these families who have this mutation have hypercholesterolemia. LDL derived from all who have inherited the mutation is dysfunctional in that it allows only poor growth of an LDL cholesterol-dependent cell line. We conclude that this arginine 3500 is essential to the function of apoB and that its loss and replacement by glutamine or tryptophan is responsible for the hypercholesterolemia of familial defective apoB 100.

The affinity of low-density lipoproteins and of very-low-density lipoprotein remnants for the low-density lipoprotein receptor in homozygous familial defective apolipoprotein B-100

We have identified two familial defective apo B-100 (FDB) homozygotes by DNA sequencing and have measured affinity of low-density lipoproteins (LDL) and very-low-density lipoprotein (VLDL) remnants for the LDL receptor in vitro. The patients were a 66-year-old man with coronary heart disease (plasma cholesterol level, 9.5 mmol/l before treatment) and his 69-year-old sister, without signs of cardiovascular disease (plasma cholesterol, 12.0 mmol/l before treatment). In both patients, treatment with statins caused a marked fall in plasma cholesterol level. Binding affinity of LDL from the two patients was 10%–20% of normal at 4 °C and 37 °C. Binding affinity of VLDL remnants was normal. We conclude that (1) residual affinity of LDL in homozygous FDB is high enough to permit significant catabolism via the LDL-receptor pathway, and (2) normal affinity of VLDL remnants permits normal hepatic clearance of precursors of LDL and increased clearance of LDL precursors when receptor activity is stimulated by statins. Residual affinity of LDL and normal affinity of remnants could explain why expression of the FDB mutation is generally milder than that of LDL receptor mutations causing familial hypercholesterolaemia.

In vivo lipoprotein metabolism in a homozygous patient with familial defective apolipoprotein B-100

In vivo lipoprotein metabolism in a homozygous patient with familial defective apolipoprotein B-100

Decreased binding of recombinant apolipoprotein (a) to familial defective apolipoprotein B-100 (ARG 3500- > GLN)

Decreased binding of recombinant apolipoprotein (a) to familial defective apolipoprotein B-100 (ARG 3500- > GLN)