Missense mutations in N ‐acetylglucosamine‐1‐phosphotransferase α/β subunit gene in a patient with mucolipidosis III and a mild clinical phenotype

Abstract Mucolipidosis type III (ML III, pseudo‐Hurler polydystrophy), an autosomal recessive inherited disorder of lysosomal enzyme targeting is due to a defective N ‐acetylglucosamine 1‐phosphotransferase (phosphotransferase) activity and leads to the impaired formation of mannose 6‐phosphate markers in soluble lysosomal enzymes followed by their increased excretion into the serum. Mutations in the phosphotransferase γ subunit gene ( GNPTAG ) have been reported to be responsible for ML III. Here we report on a 14‐year‐old adolescent with a mild clinical phenotype of ML III. He presented with progressive joint stiffness and swelling. Urinary oligosaccharide and mucopolysaccharide excretion was normal. Lysosomal enzyme activities were significantly elevated in the serum and decreased in cultured fibroblasts. Impaired trafficking of the lysosomal protease cathepsin D (CtsD) was confirmed by metabolic labeling of the patient's fibroblasts. Neither mutations in the GNPTAG gene nor alterations in the GNPTAG mRNA level were detected whereas the steady state concentration of the 97 kDa GNPTAG dimer was reduced. Most importantly, the patient is homozygous for a pathogenic nucleotide substitution and a polymorphism in the phosphotransferase α/β subunit gene ( GNPTA ). The data indicate that defects in genes other than GNPTAG can be linked to ML III contributing to the variability of the phenotype. © 2005 Wiley‐Liss, Inc.