Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define thedisease sialuria and the allosteric site of the enzyme

Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic aci d (NeuAc, sialic acid). Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epi merase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuramini c acid (CMP-Neu5Ac). We report the cloning and characterization of human UD P-GlcNAc 2-epimerase cDNA, with mutation analysis of three patients with si aluria. Their heterozygote mutations, R266W; R266Q, and R263L, indicate tha t the allosteric site of the epimerase resides in the region of codons 263- 266. The heterozygous nature of the mutant allele in all three patients rev eals a dominant mechanism of inheritance for sialuria.