CHARACTERIZATION OF MUTATIONS IN THE LOW-DENSITY-LIPOPROTEIN (LDL)-RECEPTOR GENE IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA,AND FREQUENCY OF THESE MUTATIONS IN FH PATIENTS IN THE UNITED-KINGDOM

Mutations in the gene for the low density lipoprotein (LDL) receptor h ave been identified in 15 patients with homozygous familial hyperchole sterolemia (FH). Five patients are homozygous at the LDL-receptor locu s; their mutant alleles include Glu387Lys and Pro664Leu in patients of Asian-Indian descent, Cys292Stop in a Creek Cypriot, Cys281Trp in a T urkish patient, and Gln540Stop in a West Indian. The other 10 patients (9 of apparently British ancestry) are compound heterozygotes. Mutati ons have been identified in 18 of 20 possible alleles, including Glu80 Lys (2 patients), Pro664Leu (3 patients), Asp69Gly, Cys176Arg, Cys227T yr, Ser265Arg, Asp280Ala, Asp283Glu, Arg329Pro, Asp461Asn, Leu578Ser, a single bp deletion in exon 15, a 21 bp duplication of codons 200-206 and two large deletions. The seven mutations underlined above have no t been described previously. The two uncharacterized mutant alleles fa il to produce detectable amounts of mRNA. LDL-receptor activity in cul tured cells from 13 of the 15 homozygous patients varied from undetect able to about 30% of normal, but there was no correlation between LDL- receptor activity and the untreated plasma cholesterol concentration i n these patients. When genomic DNA from 295 patients with a clinical d iagnosis of FH was screened for 29 mutations found in these and other FH patients of British ancestry, most were identified in only one or a few individuals. Four patients heterozygous for the Asp461Asn allele showed a wide range of clinical manifestations. These observations con firm the striking heterogeneity underlying FH in most populations and demonstrate the variability in phenotype between patients with the sam e mutation.