title: Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia.
abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disease which results in 2-3-fold elevated cholesterol levels and in accelerated atherosclerosis. FH is caused by small mutations or larger rearrangements in the low-density lipoprotein receptor (LDLR). Here, we report that screening the LDLR gene in a Swiss family (n = 15) with clinical symptoms of FH by combined single strand conformation polymorphism and long-distance PCR identified a novel 1.3 kb deletion in the LDLR. The deletion eliminated exon 4 of the LDLR presumably by recombination between two identical 25 bp repeats present in intron 3 and 4. The 25 bp sequence in intron 3 is part of an Alu repeat, whereas no homology to Alu repeats was found for the intron 4 region. This 1.3 kb LDLR deletion allele cosegregated with elevated cholesterol levels over three generations. Even on high-dose statin therapy, carriers of the deletion averaged 1.6 times higher cholesterol levels and 1.9 times higher apolipoprotein B-100 (apoB-100) levels than non-carriers who had lipid and apoB-100 levels within the range of the Swiss population. Most affected members of the first and second generation of this family had experienced a first myocardial infarction (MI) before the age of 55 years and most LDLR gene deletion carriers older than 40 years showed severe coronary artery disease (CAD). Hence, we conclude that deletion of exon 4 in the LDLR gene drastically decreases low-density lipoprotein binding leading to severe hypercholesterolemia.
authors.affiliation: Institute of Clinical Chemistry, University Hospital, Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neff
authors.forename: Frank
authors.initials: F
authors.lastname: Ruschitzka
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Frank
authors.initials: F
authors.lastname: Enseleit
authors.forename: David
authors.initials: D
authors.lastname: Hürlimann
authors.forename: Georg
authors.initials: G
authors.lastname: Noll
authors.forename: Thomas
authors.initials: T
authors.lastname: Lüscher
authors.forename: Edgar
authors.initials: E
authors.lastname: Hänseler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics*; D013557:Switzerland / Q000453:epidemiology
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D011973:Receptors, LDL; D002784:Cholesterol