Comparative Pathology of Murine Mucolipidosis Types II and IIIC

UDP-GlcNAc: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase) is an α2β2γ2 hexameric enzyme that catalyzes the first step in the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. In humans, mutations in the gene encoding the α/β subunit precursor give rise to mucolipidosis II (MLII), whereas mutations in the gene encoding the γ subunit cause the less severe mucolipidosis IIIC (MLIIIC). In this study we describe the phenotypic, histologic, and serum lysosomal enzyme abnormalities in knockout mice lacking the γ subunit and compare these findings to those of mice lacking the α/β subunits and humans with MLII and MLIIIC. We found that both lines of mutant mice had elevated levels of serum lysosomal enzymes and cytoplasmic alterations in secretory cells of several exocrine glands; however, lesions in γ-subunit deficient (Gnptab -/-) mice were milder and more restricted in distribution than in α/β-subunit deficient (Gnptab -/-) mice. We found that onset, extent, and severity of lesions that developed in these two different knockouts correlated with measured lysosomal enzyme activity; with a more rapid, widespread, and severe storage disease phenotype developing in Gnptab -/- mice. In contrast to mice deficient in the α/β subunits, the mice lacking the γ subunits were of normal size, lacked cartilage defects, and did not develop retinal degeneration. The milder disease in the γ-subunit deficient mice correlated with residual synthesis of the mannose 6-phosphate recognition marker. Of significance, neither strain of mutant mice developed cytoplasmic vacuolar inclusions in fibrocytes or mesenchymal cells (I-cells), the characteristic lesion associated with the prominent skeletal and connective tissue abnormalities in humans with MLII and MLIII. Instead, the predominant lesions in both lines of mice were found in the secretory epithelial cells of several exocrine glands, including the pancreas, and the parotid, submandibular salivary, nasal, lacrimal, bulbourethral, and gastric glands. The absence of retinal and chondrocyte lesions in Gnptab -/- mice might be attributed to residual β-glucuronidase activity. We conclude that mice lacking either α/β or γ subunits displayed clinical and pathologic features that differed substantially from those reported in humans having mutations in orthologous genes.