Comparative Pathology of Murine Mucolipidosis Types II and IIIC

Abstract

Abstract. UDP-GlcNAc: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase) is an a 2 b 2 c 2 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 a/b subunit precursor give rise to mucolipidosis II (MLII), whereas mutations in the gene encoding the c 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 c subunit and compare these findings to those of mice lacking the a/b 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 c-subunit deficient (Gnptg 2/2 ) mice were milder and more restricted in distribution than in a/b-subunit deficient (Gnptab 2/2 ) 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 2/2 mice. In contrast to mice deficient in the a/b subunits, the mice lacking the c subunits were of normal size, lacked cartilage defects, and did not develop retinal degeneration. The milder disease in the c-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 Gnptg 2/2 mice might be attributed to residual b-glucuronidase activity. We conclude that mice lacking either a/b or c subunits displayed clinical and pathologic features that differed substantially from those reported in humans having mutations in orthologous genes.

Autophagy and pancreatitis

“…Gnptab Ϫ/Ϫ mice show a dramatic decrease in lysosomal degradative capacity of the exocrine pancreas resulting in impaired autophagy in acinar cells (Fig. 5A), manifest by numerous enlarged autolysosomes containing undigested cargo (6,105). Of note, the fusion of autophagosomes with lysosomes is not blocked in these mice (6).…”

“…An important (and different) line of evidence that dysfunctional lysosomal hydrolases, in particular cathepsins, cause autophagy impairment in acinar cells comes from studies of mice deficient in GlcNAc-1-phosphotransferase (6,56,105). This enzyme, subunits of which are coded by the Gnptab and Gnptg genes, mediates the addition of M6P moieties onto acid hydrolases, which serve as a recognition signal for specific targeting of hydrolases to the lysosome.…”

Altered Chondrocyte Differentiation and Extracellular Matrix Homeostasis in a Zebrafish Model for Mucolipidosis II

“…[21][22][23] This model is limited by the fact that early developmental processes cannot be followed in these animals due to intrauterine gestation. Kornfeld and colleagues 24,25 have also characterized a GNPTAB knockout mouse, which exhibits retinal degeneration, reduced size, and pathological lesions in several exocrine glands. Although chondrocytes from these mice were found to be hypertrophic and often distended, fibrocytes and mesenchymal cells did not develop the cytoplasmic vacuolar inclusions characteristically observed in human ML-II and ML-III patients.…”

Nephronophthisis and Retinal Degeneration inTmem218–/–Mice

“…In our experience, the appearance of very similar phenotypes (phenocopies) in either mice or humans with mutations in different genes often indicates that the proteins encoded by these mutant genes involve different steps in a common metabolic pathway or affect the same process or structure. 86,[106][107][108][109] It is often instructive to consider what is known about the underlying pathogenic mechanisms in phenocopies (whether in humans or in animal models) when attempting to understand the pathogenesis of lesions in a novel line of knockout mice. We believe that the simultaneous development of NPHP and retinal degeneration in Tmem218 -/-mice is highly suggestive of an underlying defect in the structure/function of the sensory primary cilium of renal epithelium and the connecting cilium of retinal photoreceptors, respectively.…”

“…124,125 Coincidentally, many disease phenotypes were discovered during this process, 100 and some of these have proven useful in elucidating fundamental processes in biology or in determining the underlying pathogenesis of heritable diseases. 69,75,76,79,102,[104][105][106][107][108][109][110][111] Not surprising, a large proportion of pathologic phenotypes were linked to inactivation of genes involved in the regulation of complicated and tightly controlled processes (eg, embryologic development and immunity). Many other pathologic phenotypes resulted from abnormal development of structurally complex tissues/organs (eg, eyes, teeth, sperm).…”