Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia

Myant, N. B.

doi:10.1016/0021-9150(93)90171-p

Cited by 210 publications

(101 citation statements)

References 51 publications

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“…Although the frequency of LDLR mutations was higher in paediatric cases than adults, the frequency of APOB R3500Q mutations was (non-significantly) lower in adults than in paediatric cases (15 vs 3% P50.5). Several studies have shown that FDB individuals have slightly lower cholesterol than FH individuals 6 and that cholesterol levels in FDB children become more elevated in their twenties 51 . Thus the different spectrum of mutations detected in the paediatric and adult cases is likely to be due to selection criteria.…”

Section: Mutation Spectrummentioning

confidence: 99%

“…The majority of FDB cases (2 ± 5% of hypercholesterolaemic individuals) are caused by a single mutation, R3500Q. 6 Two rare mutations are also observed, R3531C 7 and R3500W, 8 and 2.4% of Asian hypercholesterolaemic subjects are reported to have the R3500W mutation. 9 Not all cases of monogenic inherited hypercholesterolaemia are accounted for by mutations in LDLR or APOB.…”

Section: Introductionmentioning

confidence: 99%

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A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

et al. 2001

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A genetic diagnostic service for familial hypercholesterolaemia (FH) has been established over the last 4 years in the Clinical Molecular Genetics Laboratory at Great Ormond Street Hospital for Children NHS Trust (GOSH), London. In total there have been 368 referrals; 227 probands and 141 family members, which have come from a number of lipid clinics and from general practitioners. FH is caused by mutations in the lowdensity lipoprotein receptor gene (LDLR) and these are analysed by SSCP, DNA sequencing and direct assays. The clinically indistinguishable disorder, familial defective apolipoprotein B100 (FDB) is caused by one of three mutations in the apolipoprotein B100 gene (APOB) which are analysed by direct assays. Mutations predicted to be pathogenic were found in 76 probands, 67 in LDLR (23 previously undescribed) and nine in APOB. The mutation detection rate was 53% in paediatric probands, 32% in adults with a`definite' FH diagnosis (tendon xanthoma positive) and 14% in adults with a`possible' FH diagnosis (tendon xanthoma negative). The predicted loss of sensitivity that would result from reducing the number of exons tested has been assessed, and a molecular screening strategy suitable for UK patients is proposed. A similar strategy may be useful for other countries where genetic heterogeneity results in a wide mutation spectrum for FH.

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Section: Mutation Spectrummentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

et al. 2001

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“…21 It is characterized by elevated plasma total and LDLc levels and premature CHD. Three mutations (R3500Q, R3500W and R3531C) are mostly responsible for the disease by reducing the binding of LDL particles to the LDLR.…”

Section: Introductionmentioning

confidence: 99%

“…Three mutations (R3500Q, R3500W and R3531C) are mostly responsible for the disease by reducing the binding of LDL particles to the LDLR. 21,22 The R3500Q mutation was the first described and is the most prevalent, while other point mutations (R3500W and R3531C) are rare causes of FDB. 23,24 The prevalence of FDB has been estimated to be approximately 1/500 in North America, 22 whereas in Europe seems to be high in the Northwestern part of Switzerland (1/114), Eastern France and Southern Germany 22,25,26 and low in Italy and Spain.…”

Section: Introductionmentioning

confidence: 99%

“…However, the plasma LDLc levels in age-matched FDB heterozygotes vary over a wide range and, in some families, heterozygous carriers of the R3500Q mutation show normal LDLc plasma levels. 21,25 In the Spanish population, we have recently described the first FDB family and predicted a low prevalence of this disease, since only one FDB out of 113 FH index patients was detected. 26 On the contrary, and due to a founder effect in an isolated region of the Valencia province, we have been able to identify seven affected pedigrees and 19 FDB heterozygotes and one homozygote.…”

Section: Introductionmentioning

confidence: 99%

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Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population

et al. 2003

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Few data are available on genotype -phenotype interactions among familial hypercholesterolemia (FH) patients in South European populations and there are no data about the influence of R3500Q mutation on lipoprotein phenotype compared to low-density lipoprotein receptor (LDLR) mutations. The objective of the study is to analyze the influence of mutations in the LDLR and apolipoprotein B (apoB) genes on lipoprotein phenotype among subjects clinically diagnosed of FH living in East Spain. In all, 113 FH index patients and 100 affected relatives were studied. Genetic diagnosis was carried out following a protocol based on Southern blot and PCR-SSCP analysis. A total of 118 FH subjects could be classified into three groups according to the type of LDLR mutations (null mutations, missense mutations affecting the ligand binding 3-5 repeat, and missense mutations outside this domain). In addition, the lipoprotein phenotype of these FH groups was compared with 19 heterozygous subjects with familial ligand-defective apoB (FDB), due to R3500Q mutation. FH patients carrying missense mutations affecting the ligand binding repeat 3-5 showed total and LDL cholesterol levels significantly higher than FH patients with missense mutations in other LDLR domains or FDB patients. FH subjects carrying null mutations showed lower high-density lipoprotein cholesterol plasma values compared to FH carrying missense mutations. FDB subjects showed the lowest total and LDL cholesterol plasma values. In conclusion, the type of LDLR gene mutation and R3500Q mutation influences the lipoprotein phenotype of FH population from East Spain.

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

et al. 1996

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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. © 1996 Wiley‐Liss, Inc.

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Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia

Cited by 210 publications

References 51 publications

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom

Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population

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

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