A COMMON MUTATION ASSOCIATED WITH THE DUARTE GALACTOSEMIA ALLELE

The human cDNA and gene for galactose-1-phosphate uridyl transferase ( GALT) have been cloned and sequenced. A prevalent mutation (Q188R) is known to cause classic galactosemia (G/G). G/G galactosemia has an inc idence of 1/38,886 in 1,396,766 Georgia live-born infants, but a more common variant of galactosemia, Duarte, has an unknown incidence. The proposed Duarte biochemical phenotypes of GALT are as follows: D/N, D/ D, and D/G, which have similar to 75%, 50%, and 25% of normal GALT act ivity, respectively. In addition, the D allele has isoforms of its enz yme that have more acidic pI than normal. Here we systematically deter mine (a) the prevalence of an A-to-G transition at base pair 2744 of e xon 10 in the GALT gene, a transition that produces a codon change con verting asparagine to aspartic acid at position 314 (N314D), and (b) t he association of this mutation with the Duarte biochemical phenotype. The 2744G nucleotide change adds an AvaII (SinI) cut site, which was identified in PCR-amplified DNA. In 111 biochemically unphenotyped con trols with no history of galactosemia, 13 N314D alleles were identifie d (prevalence 5.9%). In a prospective study, 40 D alleles were biochem ically phenotyped, and 40 N314D alleles were found. By contrast, in 36 individuals known not to have the Duarte biochemical phenotype, no N3 14D alleles were found. We conclude that the N314D mutation is a commo n allele that probably causes the Duarte GALT biochemical phenotype an d occurs in a predominantly Caucasian, nongalactosemic population, wit h a prevalence of 5.9%.