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 ot her allele, with a substitution of Gly-99 by Asp (allele 445A), had be en identified in a Japanese adult form of MLD in a heterozygous combin ation. 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 Japan ese patients examined in this study. Analysis on the nucleotide sequen cee 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 subs titution of Gly-245 by Arg. This 1070A mutation was also found heteroz ygously in a juvenile MLD patient. When the 1070A mutation was introdu ced into the ASA cDNA and evaluated by transient expression studies, n o enzyme activity was induced. These results suggest that Japanese MLD patients have a different distribution of ASA mutations from that fou nd in a predominantly Caucasian population.