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We characterized two novel mutations of the galactose-1-phosphate uridyltransferase (GALT) gene intwo Japanese patients with GALT deficiency and identified N314D and R333W mutations, previouslyfound in Caucasians. One novel missense mutation was an G-to-A transition in exon 8, resulting in thesubstitution of arginine by histidine at the codon 231 (R231H). GALT activity of the R231H mutantconstruct was reduced to 15% of normal controls in a COS cell expression system. The other was asplicing mutation, an A-to-G transition at the 38th nucleotide in exon 3 (318AG), resulting in a38-bp deletion in the GALT cDNA by activating a cryptic splice acceptor site. In seven Japanesefamilies (14 alleles for classic form and one allele for Duarte variant) with GALT deficiency, the R231H and 318AG mutations were found only on both alleles of the proband. The N314D and R333W mutations were found on one allele each. The Q188R was prevalent in the United States butnot in Japanese patients. The N314D mutation was associated with the Duarte variant in Japanesepersons, as well as in the United States. We speculate that classic galactosemia mutations appear todiffer between Japanese and Caucasian patients. Our limited data set on galactosemia mutations in Japanese suggests that the N314D GALT mutation encoding the Duarte variant arose before Asianand Caucasian people diverged and that classic galactosemia mutations arose and/or accumulated afterthe divergence of Asian and Caucasian populations. © 1995 Wiley-Liss, Inc.