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

Abstract

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 In contrast, the incidence of FDB in this population seems to be lower than 1/500 (D.C. Rubinsztein, MD, et al, unpublished results).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.

PC9, A New Actor in Autosomal Dominant Hypercholesterolemia

“…These probands were also double mutants combining PCSK9 and LDLR gene defects. They exhibited a severe ADH phenotype, confirming the additive effect as has already been reported for APOB and LDLR double mutants [36][37][38]. Fouchier et al reported one non-LDLR/non-APOB hypercholesterolemic patient from The Netherlands that carried the A220T mutation of PCSK9, which was absent in unaffected members of the family and in 400 control subjects (AHA Scientific Sessions 2004).…”

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

“…It is also now known that 2-10% of patients with a clinical diagnosis of FH have the apoB R3500Q mutation ( 289,297,298 ), including some who also have a LDLR mutation (299)(300)(301). Compound heterozygote ADH-1/2 patients tend to have higher LDL-C, more extensive xanthomatosis, and more severe premature CHD than heterozygote ADH-1 and homozygote ADH-2 patients ( Table 6 ).…”

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

“…An intermediate phenotype between heterozygous and homozygous FH had been noted in an Afrikaner family with six compound F W D B heterozygotes carrying another LDLR mutation (Asp206Glu) (Rubinsztein et al, 1993). By contrast, a German FWFDB compound heterozygote had a phenotype quite comparable with that observed in his heterozygous relatives (Rauh et al, 1991).…”