Phenotypic heterogeneity associated with defective apolipoprotein B-100 and occurrence of the familial hypercholesterolemia phenotype in the absence of an LDL-receptor defect within a Canadian kindred.
Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg3500----Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3' hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuII(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family.(ABSTRACT TRUNCATED AT 250 WORDS)
Davignon
J
J
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada.
Dufour
R
R
Roy
M
M
Bétard
C
C
Ma
Y
Y
Ouellette
S
S
Boulet
L
L
Lussier-Cacan
S
S
D000328:Adult; D000368:Aged; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D002170:Canada; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D005260:Female; D005602:France / Q000208:ethnology; D005786:Gene Expression Regulation / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000032:analysis / Q000235:genetics*
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL