From 1972 to 1979 34 patients with homozygous familial hypercholesterolaemia were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. Their epidemiological, genetic, clinical, and biochemical characteristics were studied. The course of the disease varied considerably among the 34 patients, with no fewer than six surviving into their fourth or fifth decades. In some patients arterial atheroma was severe while cutaneotendinous xanthomas were slight and vice versa. Coronary heart disease was common but peripheral and cerebral arterial disease was rare. Another prominent finding was high concentrations of low-density lipoprotein cholesterol coupled with low high-density lipoprotein cholesterol values. The prevalences of homozygotes and heterozygotes with familial hypercholesterolaemia in Transvaal Afrikaners, calculated from this group of patients, were 1 in 30 000 and 1 in 100 respectively. These figures are the highest ever reported and may help to explain why South African whites have the
The binding and catabolism of low density lipoprotein (LDL) were studied in cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphoblastoid cells from 20 familial hypercholesterolemic (FH) homozygotes of 14 Afrikaner kindreds. Cells from available heterozygotes were also analyzed. Good resolution between the normal, heterozygote, and homozygote groups was obtained on the basis of these assays using either cell type. Results obtained with fibroblasts allowed the classification of 13 of these kindreds as being typically receptor-defective, and one kindred with two homozygotes as being receptor-negative. Fibroblasts from homozygotes of the receptor-defective class expressed LDL receptor activities which varied between 3% and 25% of normal. Where two homozygotes from the same family were available for assays (six families), both yielded similar activities. In contrast to fibroblasts, all the lymphoblastoid cells derived from FH homozygotes yielded LDL receptor activities equal to or less than 10% of normal; in a number of cases no significant
the Afrikaner population.6 Four haplotypes defined by the restriction enzymes PvuII (P), Stul (S), and NcoI (N) were found to segregate in this population. In 71% of FH families studied, the defective gene cosegregated with the rare allele of a NcoI RFLP7 (P1S1N2 haplotype), while the rare allele of a StuI RFLP8 (P2S2N1 haplotype) segregated with FH in 20% of these families. We now report on haplotype associations of 10 different DNA polymorphisms at the LDL receptor gene locus in the normocholesterolaemic and FH populations and in a large number of FH homozygotes. Subjects and methodsThe FH heterozygous patients and normocholesterolaemic subjects were those previously described.6 Pedigree analyses were performed on 27 of the 45 heterozygous FH patients and 29 of the 60 normal subjects. Blood samples were collected from 292 of the FH family members and 130 of the members from normal families. Thirty-two patients with homozygous familial hypercholesterolaemia from 27 255 on 1 May 2019 by guest. Protected by copyright.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.