MUCOPOLYSACCHARIDOSIS TYPE-I - IDENTIFICATION OF COMMON MUTATIONS THAT CAUSE HURLER AND SCHEIE SYNDROMES IN JAPANESE POPULATIONS

alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I; M PS-I) is an inborn error of lysosomal degradation of glycosaminoglycan s that results in storage of undegraded glycosaminoglycans in lysosome s. Previous studies in Caucasian populations showed that (1) homozygos ity or compound heterozygosity for the W402X and Q70X mutations are th e common causes of MPS-I with a severe form (Hurler syndrome), and (2) the presence of R89Q may lead to a milder phenotype. We studied mutat ions in the IDUA gene from 19 MPS-I patients, including two pairs of s iblings, with various clinical phenotypes (Hurler, 6 cases; Hurler/Sch eie, 7 cases; Scheie, 6 cases). We report the presence of two common m utations that account for 42% of the 38 alleles in these patients. One is a novel 5-bp insertion between the thymidine at nt 704 and a cytos ine at nt 705 (704ins5), which is seen only in the Japanese population . The other is a missense mutation, R89R, which is also seen in Caucas ians, although uncommonly. In the 19 Japanese MPS-I patients, the 704i ns5 mutation accounted for 7 of 38 alleles (18%), while the R89Q accou nted for 9 of 38 (24%). No Japanese patient was found to carry the W40 2X or Q70X alleles, the two most common MPS-I mutations in Caucasians, Homozygosity for the 704ins5 mutation is associated with a severe phe notype, and for the R89R mutation with a mild phenotype. Compound hete rozygosity for these two mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to the IDUA locus demon strated that each mutation occurs on a different specific haplotype, s uggesting that individuals with each of these common mutations derive from common founders. These data continue to document the molecular he terogeneity and racial differences in mutations in MPS-I. (C) 1996 Wil ey-Liss, Inc.