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Mucopolysaccharidosis type IVA (MPS IVA) results from a genetic deficiency of N-acetylgalactosamine-6-sulfate (Gal-NAc6S) sulfatase. We have identified two different exonic mutations causing GalNAc6S sulfatase deficiency in two unrelated Japanese families, in one patient with classical Morquio disease, and in two brothers with a mild form of MPS IVA. The nucleotide sequence of the full-length cDNA derived from a patient with classical Morquio disease revealed a two-base deletion at nucleotide position 1343-1344 (1344-1345 or 1345-1346) that altered the reading frame (designated 1342delCA). This mutation, inherited from the proband's consanguineous parents, was revealed by TaqI restriction analysis of a cDNA fragment amplified by the polymerase chain reaction. In the proband with the mild form of the disease, a C to G transversion at nucleotide 667 predicted the substitution of Lys for Asn204 (N204K). Since a new AluI site was created by the N204K mutation, restriction analysis indicated that the affected brothers were homozygous for this mutation, as confirmed by the finding that both their parents had this lesion. Transient expression in GalNAc6S sulfatase deficient fibroblasts of these two mutant alleles showed completely deficient or markedly decreased enzyme activities, thereby indicating that these two mutations were responsible for the enzyme deficiency.