A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia

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.