title: Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia.
abstract: Assessment of the apolipoprotein E (apoE) phenotype by isoelectric focusing of both hyperlipidemic and normolipidemic individuals identified five new variants. All mutations were confined to the downstream part of the APOE gene by using denaturing gradient gel electrophoresis (DGGE). Sequence analysis revealed five new mutations causing unique amino acid substitutions in the carboxyl-terminal part of the protein containing the putative lipid-binding domain. Three hyperlipoproteinemic probands were carriers of the APOE*2(Val236-->Glu) allele, the APOE*3(Cys112-->Arg; Arg251-->Gly) allele, or the APOE*1(Arg158-->Cys; Leu252-->Glu) allele. DGGE of the region encoding the receptor-binding domain was useful for haplotyping the mutations at codons 112 and 158. Family studies failed to demonstrate cosegregation between the new mutations and severe hyperlipoproteinemia, although a number of carriers for the APOE*3(Cys112-->Arg; Arg251-->Gly) allele and the APOE*1(Arg158-->Cys; Leu252-->Glu) allele expressed hypertriglyceridemia and/or hypercholesterolemia. Two other mutant alleles, APOE*4-(Cys112-->Arg; Arg274-->His) and APOE*4+(Ser296-->Arg), were found in normolipidemic probands. The lack of cosegregation of these new mutations with severe hyperlipoproteinemia suggests that these mutations do not exert a dominant effect on the functioning of apoE.
authors: Department of Human Genetics, Leiden University, The Netherlands.
authors: A M
authors: AM
authors: van den Maagdenberg
authors: W
authors: W
authors: Weng
authors: I H
authors: IH
authors: de Bruijn
authors: P
authors: P
authors: de Knijff
authors: H
authors: H
authors: Funke
authors: A H
authors: AH
authors: Smelt
authors: J A
authors: JA
authors: Gevers Leuven
authors: F M
authors: FM
authors: van't Hooft
authors: G
authors: G
authors: Assmann
authors: M H
authors: MH
authors: Hofker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006951:Hyperlipoproteinemias / Q000235:genetics*; D007525:Isoelectric Focusing; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009691:Nucleic Acid Denaturation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic
chemical_list: D001057:Apolipoproteins E