Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.31 (beta-glucuronidase)
7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lysosomal storage disorders constitute a large group of genetic diseases, many of which are characterized by mental retardation and other neurologic symptoms. The mechanisms of neural dysfunction remain poorly understood. Because neural progenitor cells (NPCs) are fundamentally important to normal brain development and function, we investigated NPC properties in a canine model of mucopolysaccharidosis VII (MPS VII). MPS VII is a lysosomal storage disorder characterized by defects in the catabolism of glycosaminoglycans. NPCs were isolated from the olfactory bulb, cerebellum, and striatal subventricular zone of normal and MPS VII (beta-glucuronidase-deficient) postnatal dog brains. Canine NPCs (cNPCs) from normal and MPS VII brains had similar growth curves, but cerebellar-derived cNPCs grew significantly slower than those derived from other regions. In differentiation assays, MPS VII cNPCs from the striatal subventricular zone and cerebellum generated fewer mature neuronal and/or glial cells than normal, and MPS VII olfactory bulb-derived cNPCs retained significantly more phenotypically immature cells. These differences were only present at the earliest time point after isolation; at later passages, there were no differences attributable to genotype. The data suggest that MPS VII cNPCs respond differently to developmental cues in vivo, probably because of the diseased neural microenvironment rather than intrinsic cellular deficits.
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PMID:Abnormalities in neural progenitor cells in a dog model of lysosomal storage disease. 1788 20

Glycosaminoglycan storage begins in prenatal life in patients with mucopolysaccharidosis (MPS). In fact, prenatal hydrops is a common manifestation of MPS VII because of beta-glucuronidase (GUS) deficiency. One way to address prenatal storage might be to deliver the missing enzyme across the placenta into the fetal circulation. Maternal IgG is transported across the placenta by the neonatal Fc receptor (FcRn), which recognizes the Fc domain of IgG and mediates transcytosis from maternal to fetal circulation. We hypothesized that we could exploit this process to deliver corrective enzyme to the fetus. To test this hypothesis, the C-terminal fusion protein, GUS-Fc, was compared with native, untagged, recombinant GUS for clearance from the maternal circulation, delivery to the fetus, and reduction of lysosomal storage in offspring of MPS VII mice. We observed that GUS-Fc, infused into pregnant mothers on embryonic days 17 and 18, was transported across the placenta. Similarly infused untagged GUS was not delivered to the fetus. GUS-Fc plasma enzyme activity in newborn MPS VII mice was 1,000 times that seen after administration of untagged GUS and approximately 100 times that of untreated WT newborns. Reduced lysosomal storage in heart valves, liver, and spleen provided evidence that in utero enzyme replacement therapy with GUS-Fc targeted sites of storage in the MPS VII fetus. We hypothesize that this noninvasive approach could deliver the missing lysosomal enzyme to a fetus with any lysosomal storage disease. It might also provide a method for inducing immune tolerance to the missing enzyme or another foreign protein.
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PMID:Infused Fc-tagged beta-glucuronidase crosses the placenta and produces clearance of storage in utero in mucopolysaccharidosis VII mice. 1854 47

Cellular transplantation in the form of bone marrow has been one of the primary treatments of many lysosomal storage diseases (LSDs). Although bone marrow transplantation can help central nervous system manifestations in some cases, it has little impact in many LSD patients. Canine models of neurogenetic LSDs provide the opportunity for modeling central nervous system transplantation strategies in brains that more closely approximate the size and architectural complexity of the brains of children. Canine olfactory bulb-derived neural progenitor cells (NPCs) isolated from dog brains were expanded ex vivo and implanted into the caudate nucleus/thalamus or cortex of allogeneic dogs. Canine olfactory bulb-derived NPCs labeled with micron-sized superparamagnetic iron oxide particles were detected by magnetic resonance imaging both in vivo and postmortem. Grafts expressed markers of NPCs (i.e. nestin and glial fibrillary acidic protein), but not the neuronal markers Map2ab or beta-tubulin III. The NPCs were from dogs with the LSD mucopolysaccharidosis VII, which is caused by a deficiency of beta-glucuronidase. When mucopolysaccharidosis VII canine olfactory bulb-NPCs that were genetically corrected with a lentivirus vector ex vivo were transplanted into mucopolysaccharidosis VII recipient brains, they were detected histologically by beta-glucuronidase expression in areas identified by antemortem magnetic resonance imaging tracking. These results demonstrate the potential for ex vivo stem cell-based gene therapy and noninvasive tracking of therapeutic grafts in vivo.
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PMID:Transplantation and magnetic resonance imaging of canine neural progenitor cell grafts in the postnatal dog brain. 1880 12

Type VII mucopolysaccharidosis is a very rare recessive lysosomal storage disease. We diagnosed a type VII MPS in a case of severe fetal hydrops after pregnancy termination at 23 weeks of gestation. The diagnosis was suspected on histopathological examination by the presence of foam cells in many viscera and foamy placental Hofbauer cells. Enzyme assay on cultured amniotic cells showed a markedly deficient beta-glucuronidase activity, thus confirming the diagnosis. This report shows the importance of a precise necropsy diagnosis in nonimmune hydrops because of putative implications for genetic counseling and prenatal diagnosis in subsequent pregnancies.
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PMID:Histopathological diagnosis of a type vii mucopolysaccharidosis after pregnancy termination. 1911 11

A 37-year-old woman presented for routine obstetrical care at 15 weeks' gestational age and the fetus was found to have hydrops fetalis. Following elective termination of the pregnancy at 18 weeks' gestational age, pathologic examination of the female conceptus revealed findings suggestive of a lysosomal storage disease within the liver and cardiac muscle. Enzyme assays for beta-galactosidase, neuraminidase, alpha-l-iduronidase, beta-glucuronidase, beta-glucosidase, Morquio disease type A enzyme, beta-fucosidase, alpha-mannosidase, and beta-mannosidase were all normal, ruling out many of the common storage diseases. Electron microscopy identified vacuoles within hepatocytes, Kupffer cells, and cardiac myocytes resembling the autophagic vacuoles characteristic of a group of diseases known as the autophagic vacuolar myopathies (AVMs). Because these diseases are exceptionally rare in females, and because such autophagic vacuoles have never before been described in liver, we propose a novel entity of "AVM-like lysosomal storage disease" presenting as nonimmune hydrops in a female fetus.
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PMID:An autophagic vacuolar myopathy-like disorder presenting as nonimmune hydrops in a female fetus. 1924 13

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase beta-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans (GAGs) within multiple organs, including the brain. Using this animal model, we compared two plasmid gene administration techniques: muscle electrotransfer and liver-directed transfer using hydrodynamic injection. We have evaluated both the expression kinetics and the biodistribution of beta-glucuronidase activity after gene transfer, as well as the correction of biochemical abnormalities in various organs. This study shows that MPS VII mice treated with a plasmid-bearing mouse beta-glucuronidase cDNA, acquire the ability to produce the beta-glucuronidase enzyme for an extended period of time. The liver seemed to be more appropriate than the muscle as a target organ to enable enzyme secretion into the systemic circulation. A beneficial effect on the MPS VII pathology was also observed, as liver-directed gene transfer led to the correction of secondary enzymatic elevations and to the reduction of GAGs storage in peripheral tissues and brain, as well as to histological correction in many tissues. This work is one of the first examples showing that non-viral plasmid DNA delivery can lead to improvements in both peripheral and brain manifestations of MPS VII disease. It confirms the potential of non-viral systemic gene transfer strategy in neurological lysosomal disorders.
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PMID:Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery. 1935 15

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease in which deficiency in beta-glucuronidase results in glycosaminoglycan (GAG) accumulation in and around cells, causing shortened long bones through mechanisms that remain largely unclear. We demonstrate here that MPS VII mice accumulate massive amounts of the GAG chondroitin-4-sulfate (C4S) in their growth plates, the cartilaginous region near the ends of long bones responsible for growth. MPS VII mice also have only 60% of the normal number of chondrocytes in the growth plate and 55% of normal chondrocyte proliferation at 3weeks of age. We hypothesized that this reduction in proliferation was due to C4S-mediated overactivation of fibroblast growth factor receptor 3 (FGFR3). However, MPS VII mice that were FGFR3-deficient still had shortened bones, suggesting that FGFR3 is not required for the bone defect. Further study revealed that MPS VII growth plates had reduced tyrosine phosphorylation of STAT3, a pro-proliferative transcription factor. This was accompanied by a decrease in expression of leukemia inhibitory factor (LIF) and other interleukin 6 family cytokines, and a reduction in phosphorylated tyrosine kinase 2 (TYK2), Janus kinase 1 (JAK1), and JAK2, known activators of STAT3 phosphorylation. Intriguingly, loss of function mutations in LIF and its receptor leads to shortened bones. This suggests that accumulation of C4S in the growth plate leads to reduced expression of LIF and reduced STAT3 tyrosine phosphorylation, which results in reduced chondrocyte proliferation and ultimately shortened bones.
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PMID:Mechanism of shortened bones in mucopolysaccharidosis VII. 1937 67

We report on the detection of discordant inclusions in the brain of a 25-week female fetus with a very rare lysosomal storage disease, namely, Sly disease (mucopolysaccharidosis (MPS) type VII), presenting with nonimmune hydrops fetalis. Besides vacuolated neurons, we found abundant deposition of polyglucosan bodies (PGBs) in the developing brain of this fetus in whom MPS-VII was corroborated by lysosomal beta-glucuronidase-deficiency detected in fetal blood and fetal skin-fibroblasts and by the presence of a heterozygous pathogenic variant in the GUSB gene in the mother. Fetal/neonatal metabolic disorders with PGB-deposition are extremely rare (particularly in relation to CNS involvement) and include almost exclusively subtypes of glycogenosis (types IV and VII). The accumulation of PGBs (particularly in the fetal brain) has so far not been depicted in Sly disease. This is the first report on such "aberrant" association. Besides, the detection of these CNS inclusions at such an early developmental stage is remarkably unique.
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PMID:First Report on Fetal Cerebral Polyglucosan Bodies in Mucopolysaccharidosis Type VII. 2877 Jan 19


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