IDENTIFICATION OF RECURRENT AND NOVEL MUTATIONS IN EXON 4 OF THE LDL RECEPTOR GENE IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE UNITED-KINGDOM

A group of 200 patients with familial hypercholesterolemia (FH) who were attending lipid clinics in the London area have been screened for four known point mutations and a microdeletion in exon 4 of the low density lipoprotein receptor gene by polymerase chain reaction (PCR) amplification of genomic DNA and either enzyme digestion of the product or hybridization with allele-specific oligonucleotides. A point mutation of Ser156 --> Leu that was initially described in a Puerto Rican family was found in one patient of Polish origin on a different haplotype from that described originally and thus is likely to have occurred independently. A 3-bp deletion that causes deletion of amino acid Gly197 was found in six of the patients, who were all of Jewish origin and who shared the same haplotype for the mutant allele. A mutation of Asp206 --> Glu that has been described in the Afrikaner population was found in three patients, two of UK origin and one a recent immigrant from South Africa. In all cases the haplotype of the mutant allele was compatible with that described in the original patient. The mutations at Asp154 reported in South African patients and at Glu207 reported in French Canadian patients were not detected in this sample. However, two additional mutations have been identified in this sample: the first, a 2-bp deletion in codon 206 that was found in five patients, all of British ancestry, and the second, a point mutation in a single patient of Irish origin that creates a stop codon at residue Cys210. Of the 200 FH patients in the sample, the molecular defect in 16 (8%) could be detected by PCR using three different tests. Thus, based on the results from analysis of exon 4, the data suggest that during screening of FH patients who have been selected from a population of heterogeneous origin, only a limited spectrum of reported mutations will be found and the occurrence of the same mutation in different patients does not necessarily imply that they share a common ancestor, especially for those mutations occurring at 5'-CpG-3' dinucleotides.