Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

In order to identify mutations in the low density lipoprotein receptor (LDLR) gene in primary hypercholesterolemia, we screened 100 unrelated German individuals with elevated plasma LDL-C (LDL-C > 4,7 mmol/l) for mutations in the 18 exons and their flanking intronic sequences including the promoter region of the LDL-R gene using a combination of polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE) and direct sequencing. In addition we tested all patients for the presence of mutations in codons 3456 - 3553 of the gene encoding apolipoprotein B-100. In 56 individuals we detected 37 different mutations affecting the LDL-R gene, 16 of which, designated C122R, C127Y, C163W, F179L, R236W, E296X, R553C, V618D, T721I, V785D, G1358+2A, 257delTCTGGAGGT, 657delC, 676insACGGTATGGACTGCAdelGACG, C1205delTCT, 2420delTCCTTCT, have not yet been reported. One proband was a compound heterozygote showing two separate sequence variations (E207X and T705I). Seven patients were heterozygous for the mutation R3500Q within the apoB-100 gene. These results demonstrate that there is a broad spectrum of mutations in the LDL-R gene and that the R3500Q mutation is a frequent cause of hypercholesterolemia in the German population.