MUTATION AND HAPLOTYPE ANALYSES OF THE WERNERS-SYNDROME GENE BASED ONITS GENOMIC STRUCTURE - GENETIC EPIDEMIOLOGY IN THE JAPANESE POPULATION

The correlation between mutations in the Werner's syndrome (WRN) gene and the haplotypes of surrounding markers was studied in Japanese pati ents. We have elucidated the genomic structure of WRN helicase, and fo und five additional mutations, designated mutations 6-10. Mutations 4 and 6 were found to be the two major mutations in this population; the se mutations comprised 50.8% and 17.5%, respectively, of the total in a sample of 126 apparently unrelated chromosomes. Almost all the patie nts homozygous for mutation 4 shared a haplotype around the WRN gene, consistent with the view that they are derived from a single ancestor. This important advantage demonstrated in the identification of the WR N gene suggests that the Japanese present a unique population for the cloning of other disease genes. The conserved haplotype was observed a cross 19 loci, extending a distance estimated to be more than 1.4 Mbp around the WRN gene. This haplotype is rare among random Japanese indi viduals. Unexpectedly, all the nine patients homozygous for mutation 6 shared a haplotype that was identical to this haplotype at 18 of thes e 19 markers. These results suggest that mutations 4 and 6 arose indep endently in almost identical rare haplotypes. The remaining mutations (1, 5, 7, 8, 9, and 10) occurred rarely, and were each associated with different haplotypes.