Abstract
Monogenically inherited hypercholesterolemia is most commonly caused by mutations at the low density lipoprotein receptor (LDLR) locus causing familial hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the disorder familial defective apoB (FDB). Probands from 47 kindreds with a strict clinical diagnosis of FH were selected from the Cardiovascular Genetics Research Lipid Clinic, Utah, for molecular genetic analysis. Using a combination of single-strand conformation polymorphism (SSCP) and direct sequencing, 12 different LDLR gene mutations were found in 16 of the probands. Three of the probands were carriers of the APOB R3500Q mutation. In five of the remaining 28 pedigrees where no mutation had been detected, samples from enough relatives were available to examine co-segregation with the LDLR region using the microsatellite marker D19S221, which is within 1 Mb centromeric of the LDLR locus, and D19S394, sited within 150 kb telomeric of the LDLR locus. In four of the families there was strong evidence for co-segregation between the LDLR locus and the phenotype of hypercholesterolemia, but in one large family with 18 living affected members and clear-cut bimodal hypercholesterolemia, there were numerous exclusions of co-segregation. Using length polymorphic markers within and outside the APOB gene, linkage of phenotype in this family to the APOB region was similarly excluded. In this large family, the degree of hypercholesterolemia, prevalence of tendon xanthomata, and occurrence of early coronary disease were indistinguishable from the other families studied. In summary, the data provide unequivocal evidence that a third locus can be etiological for monogenic familial hypercholesterolemia and should be reinvigorating to research in this field.—Haddad, L., I. N. M. Day, S. Hunt, R. R. Williams, S. E. Humphries, and P. N. Hopkins. Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred. J. Lipid Res. 1999. 40: 1113–1122.
Highlights
Inherited hypercholesterolemia is most commonly caused by mutations at the low density lipoprotein receptor (LDLR) locus causing familial hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the disorder familial defective apoB (FDB)
Segregation of severely elevated plasma low density lipoprotein cholesterol levels, tendon xanthomata, and premature coronary disease occur in the well-recognized disorder of familial hypercholesterolemia (FH)
These included those with total cholesterol above 300 mg/dl from records of state and local health department screening of 75,000 persons, hospital data identifying over 5,000 persons discharged with diagnosis of coronary heart disease (CHD) before age 55, shopping mall cholesterol screening of 7,000 persons, referrals from responses to a letter sent to 720 primary care physicians in Utah asking them to identify patients with FH, and “Health Family Tree” questionnaires collected from the parents of 80,000 high school students in Utah [31]
Summary
Inherited hypercholesterolemia is most commonly caused by mutations at the low density lipoprotein receptor (LDLR) locus causing familial hypercholesterolemia (FH) or at the apolipoprotein B (APOB) locus causing the disorder familial defective apoB (FDB). Using length polymorphic markers within and outside the APOB gene, linkage of phenotype in this family to the APOB region was excluded In this large family, the degree of hypercholesterolemia, prevalence of tendon xanthomata, and occurrence of early coronary disease were indistinguishable from the other families studied. Evidence for a third genetic locus causing familial hypercholesterolemia: a non-LDLR, non-APOB kindred. ApoB defects in receptor binding remained a plausible cause of familial hypercholesterolemic phenotype [1], and an example was presented [4] and subsequently shown to involve a specific mutation, R3500Q in APOB [5]. It is assumed but not proven that in each instance the failure is technical, due, for example, to insensitive methods or not all of the gene having been examined, e.g., introns
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