Mutations in the arylsulfatase A gene of Japanese patients with metachromatic leukodystrophy.

To understand the molecular basis of metachromatic leukodystrophy (MLD) in Japanese patients, we analyzed the presence of three known mutant arylsulfatase A (ASA) alleles in 9 Japanese patients with MLD. Two of these mutant alleles (designated 609A and 2381T) were reported to be relatively frequent in a sample of predominantly Caucasian MLD. The other allele, with a substitution of Gly-99 by Asp (allele 445A), had been identified in a Japanese adult form of MLD in a heterozygous combination. We have found that allele 445A has a moderately high incidence among Japanese patients with MLD, and that homozygosity results in the late-infantile form. Neither allele 609A nor 2381T was found in Japanese patients examined in this study. Analysis on the nucleotide sequence of the ASA genes from another late-infantile MLD patient revealed the presence of a previously unreported G-to-A mutation at the 1,070th nucleotide of the ASA gene (designated 1070A). This results in a substitution of Gly-245 by Arg. This 1070A mutation was also found heterozygously in a juvenile MLD patient. When the 1070A mutation was introduced into the ASA cDNA and evaluated by transient expression studies, no enzyme activity was induced. These results suggest that Japanese MLD patients have a different distribution of ASA mutations from that found in a predominantly Caucasian population.