HOMOZYGOSITY MAPPING OF THE WERNER SYNDROME LOCUS (WRN)

Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mix ed ethnic origins, 26 of which were consanguineous. In 24 of these fam ilies, the affected subject was given the diagnosis of ''definite'' WS and affected subjects in the remaining 3 pedigrees were given the dia gnosis of ''probable'' WS. Affected subjects from each kindred were ge notyped for 13 short tandem repeat polymorphic sites. Two-point linkag e analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, FLAT, D8S165, and D8S166. The locus yielding a maximum lod sco re at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Z(max) greater than or equal to 3 .0) for both Japanese and non-Japanese (mostly Caucasian) families, de monstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17 .05 at a distance of approximately 0.6 cM from D8S339. The combined ev idence from a-point analysis, multipoint analysis, and analysis of reg ions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval conta ining D8S339. (C) 1994 Academic Press, Inc.