Novel mutations of the LDL receptor gene in familial hypercholesterolemia pedigrees in Hokkaido

In the course of investigations of familial coronary artery disease in Hokkaido, the northern island of Japan, we identified five families in which multiple members showed elevated plasma levels of LDL cholesterol. To determine the genetic etiology of their lipoprotein abnormalities, we screened DNA samples from these families for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein receptor (LDLR) gene. Novel point mutations were identified in each family: (1) a C-to-A transversion at nucleotide 285, causing a nonsense mutation at codon 74, in eight members of family A; (2) a G-to-A transition at nucleotide 1136, causing substitution of Tyr for Cys at codon 358, in six members of family B; (3) a C-to-T transition at nucleotide 1822, causing substitution of Ser for Pro at codon 587, in five members of family C; (4) a one-base insertion of G to a five-G stretch at 1774-8 (codons 571-572), causing a frameshift, in six members of family D; (5) a one-base deletion of T at nucleotide 1963-4 (codon 634), causing a frameshift, in three members of family E. Through the molecular genetic approach a total of 28 individuals were diagnosed unequivocally as heterozygous for the respective LDLR mutations in these families. This method also helped us to diagnose with FH, or to exclude from carrier status, eleven children with borderline high cholesterol levels.