Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases

Tybjærg‐Hansen, Anne; Gallagher, John J.; Vincent, John B.; Houlston, Richard S.; Talmud, Philippa J.; Dunning, Alison M.; Seed, Mary; Hamsten, Anders; Humphries, Steve E.; Myant, N. B.

doi:10.1016/0021-9150(90)90031-d

Cited by 146 publications

(47 citation statements)

References 11 publications

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“…Therefore, the contribution of this mutation was estimated at only 6% in the sample of ADH families. This is in agreement with other European populations as reported by Tybjaerg-Hansen et al, 42 Talmud et al, 43 Miserez et al 44 and Rabès et al 37 The discrepancy can be explained by the rather large confidence interval associated with the results of the HOMOG tests for the APOB gene markers (Table 2). However, since the genetic approach we used analyses the possible involvement of a candidate gene and not of a single mutation, our sample could contain a few families carrying still unidentified hypercholesterolaemic mutations of the APOB gene.…”

Section: Discussionsupporting

confidence: 91%

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

et al. 2000

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Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR / non APOB' families.

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Section: Discussionsupporting

confidence: 91%

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

et al. 2000

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“…A mutant apoB 3500 in three patients from group III and four patients from group II was verified by allele-specific oligonucleotide mutants and, additionally, by the competition assay shown in Fig 7. The frequency of the apoB 3500 mutation among our hypercholesterolemic patients is about 3%, similar to that observed among other western European populations. 19 On the basis of their medical history, four patients had secondary forms of hypercholesterolemia due to endocrinologic disorders. Twentytwo patients seemed to have nongenetic, dietary-induced hypercholesterolemia.…”

Section: -51mentioning

confidence: 99%

Fluorescence flow cytometry of human leukocytes in the detection of LDL receptor defects in the differential diagnosis of hypercholesterolemia.

Schmitz

Brüning

Kovács

et al. 1993

Arterioscler Thromb

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A flow-cytometric method with fluorescence-labeled monoclonal antibodies (MABs) against the low density lipoprotein (LDL) receptor (C7A MAB) or 3,3'-dioctadecylindocarbocyanin-iodide (Dil) LDL has been developed that allows the quantification of LDL receptors on leukocytes and the identification of patients with familial hypercholesterolemia (FH) within 48 hours. Leukocytes were isolated from 10 mL anticoagulated blood by density gradient centrifugation. To induce maximal expression of LDL receptors, mononuclear cells were preincubated with either phytoheraagglutinine (PHA) or iipoprotein-deflcient serum (LPDS). LPDS-treated raonocytes provided a more homogeneous cell population with regard to LDL receptor activity than did the PHA-treated lymphocytes; they also provided a greater discrimination between the fluorescence of the receptor probes and cellular autofluorescence. The C7A MAB was able to compete for Dil LDL binding by about 40%. In competition with unlabeled LDL, Dil LDL revealed linear binding, indicating an affinity similar to native LDL. The binding characteristics of Dil LDL were also similar to IZ5 I-LDL binding. LDL isolated from familial defective apolipoprotein B-100 was not able to compete for Dil LDL binding on monocytes, whereas native LDL reduced it by about 80%. In monocytes from FH heterozygous patients, the cellular mean fluorescence using either C7A MAB or Dil LDL at 4°C was 30% to 70%; in FH homozygotes, cellular mean fluorescence was less than 20% of that in monocytes from normal individuals. In patients with familial defective apolipoprotein B-100 antibody binding was normal, but one patient's own LDL failed to compete with normal Dil LDL for 4°C binding on U937 test monocytes. Patient monocytes having internalization defects showed normal 4°C Dil LDL binding, but at 20°C cell-associated fluorescence was reduced by about 40%. In our study 384 hypercholesterolemic patients (preselected according to serum cholesterol levels, clinical symptoms, and family history) were analyzed for LDL receptor expression using the C7A MAB-based assay. In 71.8% of the patients with cholesterol levels higher than 300 mg/dL, an LDL receptor deficiency was observed. Apolipoprotein E isofonns and lipoprotein [a] were found to be independent from the LDL receptor status. In some patients with high cholesterol levels but normal LDL receptor expression with the C7A MAB assay, LDL receptor defects could be diagnosed when either reduced binding or internalization of Dil LDL or familial defective apolipoprotein B-100 was detected. We conclude that fluorescence flow cytometry provides an appropriate, easily performed assay system for the differential diagnosis of LDL receptor defects, including LDL receptor deficiencies and internalization defects, and also allows the discovery of ligand defects.

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“…3 Although initial reports suggested that FDB is a milder disease than FH, 2 subsequent studies have indicated that the clinical and biochemical sequelae of these two genetic disorders are often very similar. 4 - 5 In addition, patients with FDB apparently respond to the same extent as those with FH to lipid-lowering drugs that upregulate LDL receptors. 6 The Afrikaner population in South Africa has a particularly high incidence (=1/70) of monogenic hypercholesterolemia 7 that is largely but not completely accounted for by three founder LDL receptor mutations, the so-called FH Afrikaner-1, -2, and -3 mutations.…”

Section: F Amilial Defective Apolipoprotein (Apo) B-100mentioning

confidence: 99%

Characterization of six patients who are double heterozygotes for familial hypercholesterolemia and familial defective apo B-100.

Rubinsztein

Raal

Seftel

et al. 1993

Arterioscler Thromb

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Familial defective apolipoprotein B-100 (FDB) and familial hypercholesterolemia (FH) are the common causes of monogenic primary hypercholesterolemia. An individual of mixed English and Afrikaner descent with both FDB and the FH Afrikaner-1 low-density lipoprotein receptor mutation was identified in our laboratory. Subsequent analysis of her extended family revealed the presence of heterozygotes for either FH Afrikaner-1, FH Afrikaner-2, or FDB as well as five additional double heterozygotes for FH Afrikaner-1 and FDB and one "complex" heterozygote with all three mutations. The hypercholesterolemic and clinical features of the pure FDB subjects were similar to those of the pure FH heterozygotes. The Afrikaner population in South Africa has a particularly high incidence (=1/70) of monogenic hypercholesterolemia 7 that is largely but not completely accounted for by three founder LDL receptor mutations, the so-called FH Afrikaner-1, -2, and -3 mutations. In contrast, the incidence of FDB in this population seems to be lower than 1/500 (D.C. Rubinsztein, MD, et al, unpublished results). In this study we have identified a large family of mixed English and Afrikaner descent that is characterized by the presence of both the FDB as well as FH Afrikaner-1 and Afrikaner-2 LDL receptor mutations.In addition to heterozygotes for either the FH Afrikaner-1, FH Afrikaner-2, or FDB mutations, six individuals who are double heterozygotes for the FH Afrikaner-1 and FDB mutations were identified, as well as one "complex" heterozygote who possessed all three mutations. This large pedigree allowed the clinical comparison of these various genotypes and their combinations within a single kindred. Methods PatientsPatients attended the Lipid Clinic at the Johannesburg General Hospital. Blood was obtained with informed consent and appropriate institutional approval. DNA IsolationDNA isolation from blood was carried out as described by Talmud et al. 11 Detection of Mutations and Isotyping of Apo E PolymorphismsThree founder-type mutations, FH Afrikaner-1, -2, and -3, together account for more than 80% of FH in Afrikaners. FH Afrikaner-1 (an Asp^ to Glu substitution) results in receptors that are slowly processed from the precursor to the mature form.

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Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases

Cited by 146 publications

References 11 publications

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

Fluorescence flow cytometry of human leukocytes in the detection of LDL receptor defects in the differential diagnosis of hypercholesterolemia.

Characterization of six patients who are double heterozygotes for familial hypercholesterolemia and familial defective apo B-100.

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