COMMON MUTATIONS IN THE LOW-DENSITY-LIPOPROTEIN-RECEPTOR GENE CAUSINGFAMILIAL HYPERCHOLESTEROLEMIA IN THE JAPANESE POPULATION

Familial hypercholesterolemia (FH) is a common genetic disorder caused by mutations of the LDL-receptor gene. In the present study, we inves tigated four Japanese FH homozygotes and identified five point mutatio ns: a splice site mutation in intron 12 (the 1845+2 T-->C mutation), a missense mutation in exon 7 (the C317S mutation), a nonsense mutation in exon 17 (the K790X mutation), a missense mutation in exon 14 (the P664L mutation), and a missense mutation in exon 4 (the E119K mutation ). We developed simple methods for detecting these mutations. When we examined the presence of these mutations in 24 unrelated FH homozygote s, the 1845+2 T-->C mutation was found in 7 of them, and the other fou r mutations were unique for each proband. We also screened 120 unrelat ed FH heterozygotes for these mutations and found that the frequencies of the 1845+2 T-->C, C317S, K790X, P664L, and E119K mutations were 13 .3% (16/120), 6.7% (8/120), 6.7% (8/120), 3.3% (4/120), and 1.7% (2/12 0), respectively. These mutations were found in more than 30% of unrel ated Japanese FH patients. By using the detection methods developed in this study, the diagnosis of more than 30% of the genetic bases of Ja panese FH heterozygotes is expected.