title: A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia.
abstract: Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disorder characterized by high serum low-density lipoprotein (LDL)-cholesterol concentrations, xanthoma formation, and premature atherosclerosis. Homozygous individuals die of vascular disease as children or young adults; heterozygous persons are at high risk for premature cardiovascular death. Mutations in the LDL-receptor gene are responsible for FH. We studied 49 members of a consanguineous Syrian kindred containing 6 homozygous individuals from the same pedigree. Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (> 14 mmol/l). Heterozygous FH individuals from this family were also clearly distinguishable with respect to xanthoma size. We performed DNA analysis and were successful in identifying a hitherto not described mutation in this family's LDL receptor. DNA sequence analysis of the LDL-receptor gene revealed a T to C substitution at nucleotide 1,999 in codon 646 of exon 14. We next conducted a segregation analysis, which suggests that a susceptibility gene may explain the formation of giant xanthomas in this family. We raise the hypothesis that the appearance of giant xanthomas in this FH family is controlled by a second gene acting in an autosomal-dominant or recessive fashion. Elucidation of this 'xanthoma' gene may shed additional light on LDL-cholesterol deposition.
authors.affiliation: Franz Volhard Clinic, Virchow Klinikum, Humboldt University of Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Vergopoulos
authors.forename: T
authors.initials: T
authors.lastname: Bajari
authors.forename: M
authors.initials: M
authors.lastname: Jouma
authors.forename: H
authors.initials: H
authors.lastname: Knoblauch
authors.forename: A
authors.initials: A
authors.lastname: Aydin
authors.forename: S
authors.initials: S
authors.lastname: Bähring
authors.forename: B
authors.initials: B
authors.lastname: Mueller-Myhsok
authors.forename: A
authors.initials: A
authors.lastname: Dresel
authors.forename: R
authors.initials: R
authors.lastname: Joubran
authors.forename: F C
authors.initials: FC
authors.lastname: Luft
authors.forename: H
authors.initials: H
authors.lastname: Schuster
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D008078:Cholesterol, LDL / Q000097:blood; D003241:Consanguinity; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D013593:Syria; D014973:Xanthomatosis / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL