title: A common W556S mutation in the LDL receptor gene of Danish patients with familial hypercholesterolemia encodes a transport-defective protein.
abstract: In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH.
authors.affiliation: Center for Medical Molecular Biology, Aarhus University Hospital, Skejby Sygehus, Arhus N, Denmark. hkj@post4.tele.dk
authors.forename: H K
authors.initials: HK
authors.lastname: Jensen
authors.forename: H
authors.initials: H
authors.lastname: Holst
authors.forename: L G
authors.initials: LG
authors.lastname: Jensen
authors.forename: M M
authors.initials: MM
authors.lastname: Jørgensen
authors.forename: P H
authors.initials: PH
authors.lastname: Andreasen
authors.forename: T G
authors.initials: TG
authors.lastname: Jensen
authors.forename: B S
authors.initials: BS
authors.lastname: Andresen
authors.forename: F
authors.initials: F
authors.lastname: Heath
authors.forename: P S
authors.initials: PS
authors.lastname: Hansen
authors.forename: S
authors.initials: S
authors.lastname: Neve
authors.forename: K
authors.initials: K
authors.lastname: Kristiansen
authors.forename: O
authors.initials: O
authors.lastname: Faergeman
authors.forename: S
authors.initials: S
authors.lastname: Kølvraa
authors.forename: L
authors.initials: L
authors.lastname: Bolund
authors.forename: N
authors.initials: N
authors.lastname: Gregersen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017124:Conserved Sequence; D003718:Denmark; D005091:Exons; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D018613:Microscopy, Confocal; D017354:Point Mutation; D011973:Receptors, LDL / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D012694:Serine; D014162:Transfection; D014364:Tryptophan
chemical_list: D011973:Receptors, LDL; D012694:Serine; D014364:Tryptophan