Identification of a variant of mucolipidosis III (pseudo-Hurler polydystrophy): a catalytically active N-acetylglucosaminylphosphotransferase that fails to phosphorylate lysosomal enzymes.

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Abstract
Fibroblasts from patients with I-cell disease (mucolipidosis II) or with pseudo Hurler polydystrophy (mucolipidosis III) are markedly deficient in UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. As a consequence, the common phosphomannosyl recognition marker of acid hydrolases is not generated and these enzymes are not targeted to lysosomes. A sensitive assay for the transferase was developed that uses .alpha.-methyl mannoside as an acceptor and distinguishes between fibroblasts from these 2 types of patients. The enzyme activity is less in the former than in the latter (< 0.4-2.0 pmol/mg per h vs. 2.9-39.4). This may provide an explanation for the difference in clinical severity between the 2 syndromes. However, in 2 siblings with pseudo Hurler polydystrophy (GM 3391 and GM 3392), the enzyme activity was normal when assayed by using .alpha.-methyl mannoside as acceptor whereas it was low when assayed with endogenous glycoprotein acceptors or with human placental .beta.-hexosaminidase A. The apparent Km values of the mutant enzyme toward .alpha.-methyl mannoside, high-mannose oligosaccharides, and UDP-GlcNAc were not different from those of the normal enzyme. Mixing experiments demonstrated that the mutant fibroblasts contained endogenous acceptors and were free of inhibitors. The N-acetylglucosaminylphosphotransferase in the mutant fibroblasts has normal catalytic activity but is defective in the ability to recognize lysosomal enzymes as specific substrates for phosphorylation. This variant form of pseudo Hurler polydystrophy demonstrates the biological importance of this recognition mechanism in the generation of the phosphomannosyl marker.

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