FAMILIAL LIGAND-DEFECTIVE APOLIPOPROTEIN B-100 - DETECTION, BIOCHEMICAL FEATURES AND HAPLOTYPE ANALYSIS OF THE R3531C MUTATION IN THE UK

Familial ligand-defective apolipoprotein (apo) B-100 (FDB) is an autos omal codominant disorder which may give rise to hypercholesterolaemia. It is caused by the substitution of glutamine for arginine at codon 3 500 of the apo B gene (apo B R3500Q), resulting in decreased binding o f low density lipoprotien (LDL) to the LDL receptor. In order to searc h for other mutations in this region of the apo B gene, we have screen ed genomic DNA, obtained from 412 hypercholesterolaemic individuals, u sing heteroduplex analysis. Additional heteroduplex bands were observe d following analysis of DNA from 11 individuals, nine of whom were het erozygous for apo B R3500Q: The two remaining individuals, both of Cel tic origin, were shown by DNA sequencing to be heterozygous for a C -- > T transition, at nucleotide 10 800 of the apo B gene, resulting in t he substitution of cysteine for arginine at codon 3531 (ape B R3531C). Both had a strong family history of atherosclerosis and family studie s revealed a further four individuals heterozygous for the mutation, t hree of whom were hypercholesterolaemic. Individuals heterozygous for apo B R3531C and R3500Q had mean +/- S.E.M. cholesterol concentrations of 7.82 +/- 0.68 and 8.53 +/- 0.31 mmol/l, respectively. These values were significantly higher than the value of 5.51 +/- 0.23 mmol/l obse rved in their unaffected relatives. These findings suggest that apo B R3531C is both less common in the UK and gives rise to a less severe f orm of hypercholesterolaemia than the classical 3500 mutation. In one of the families, the R3531C mutation occurred on a haplotype, compatib le with that previously assigned to the mutation in a North American f amily also of Celtic origin. This is consistent with the mutation havi ng been inherited from a common distant ancestor in individuals of Cel tic origin. (C) 1997 Elsevier Science Ireland Ltd.