Disease relevance of Gaucher Disease

• OBJECTIVE: To evaluate an educational, counseling, and carrier testing program for 3 genetic disorders: Tay-Sachs disease (TSD), type 1 Gaucher disease (GD), and cystic fibrosis (CF) that differ in detectability, severity, and availability of therapy [1].
• Pulmonary hypertension in type 1 Gaucher's disease. Comité d'Evaluation du Traitement de la Maladie de Gaucher [2].
• Elevated levels of serum angiotensin-converting enzyme have now been associated with three diseases states: sarcoidosis, Gaucher's disease, and leprosy [3].
• Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid beta-glucosidase locus [4].
• To overcome this, a bicistronic recombinant retrovirus has been generated that delivers both a therapeutic glucocerebrosidase (GC) cDNA for the treatment of Gaucher disease, and a small murine cell surface antigen (heat-stable antigen [HSA]) as a selectable marker [5].

High impact information on Gaucher Disease

• Short-term effects of pamidronate in patients with Gaucher's disease and severe skeletal involvement [6].
• A less costly regimen of alglucerase to treat Gaucher's disease [7].
• Elevation of serum angiotensin-converting enzyme in Gaucher's disease [8].
• Increased circulating levels of transcobalamin ii in gaucher's disease [9].
• Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene [10].

Chemical compound and disease context of Gaucher Disease

• Mannose-terminated glucocerebrosidase (alglucerase; Ceredase) was designed for enzyme replacement therapy in Gaucher disease to take advantage of mannose receptor-mediated endocytosis by macrophages [11].
• Treatment of Gaucher's disease with OGT 918 [12].
• METHODS: We examined the uptake and tissue distribution of radiolabelled enzyme molecules by gamma scintigraphy after bolus injection of iodine-123-labelled recombinant or placental enzyme (imiglucerase and alglucerase, respectively) in eight patients with type 1 Gaucher's disease, and in one healthy individual [13].
• Saposin A, a heat-stable 16-kDa glycoprotein, was isolated from Gaucher disease spleen and purified to homogeneity [14].
• The NN-DNJ chaperone also increases WT beta-Glu activity, but not that of L444P, a less prevalent Gaucher disease variant [15].

Biological context of Gaucher Disease

• These results indicate that no firm correlation exists between the type or degree of abnormal processing of acid beta-glucosidase in fibroblasts and the phenotype of Gaucher disease [16].
• These data and the low residual activity of the enzyme in all the variants of Gaucher disease suggest that the mutations of beta-glucocerebrosidase are allelic and involve the active site [17].
• Exhaustive screening of the acid beta-glucosidase gene, by fluorescence-assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease [18].
• Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene [19].
• The N370S mutation at the GBA locus on human chromosome 1q21, which causes Gaucher disease (GD), has a high frequency in the Ashkenazim and is the second-most-widespread GD mutation in the European non-Jewish population [20].

Anatomical context of Gaucher Disease

• We report herein that the addition of subinhibitory concentrations (10 microM) of N-(n-nonyl)deoxynojirimycin (NN-DNJ) to a fibroblast culture medium for 9 days leads to a 2-fold increase in the activity of N370S beta-Glu, the most common mutation causing Gaucher disease [15].
• Although excessive storage of glucosylceramide in histiocytes is pathognomonic for Gaucher disease, we found that Gaucher disease fibroblasts contained 1.23 +/- 0.08 nmol of glucosylceramide/mg cell protein; normal infant cells, 1.11 +/- 0.48 [21].
• Glucocerebrosidase from normal human spleen, and spleen from cases of neurologic (types 2 and 3) and nonneurologic (type 1) Gaucher's disease, was delipidated and inactivated by extraction from membranes with sodium cholate and ice-cold 1-butanol [22].
• Here we describe a mouse model of Gaucher disease which has a chemically induced deficiency of glucocerebrosidase and that accumulates elevated levels of glucosylceramide (GL-1) in the lysosomes of Kupffer cells [23].
• Studies in leukocytes, cultured skin fibroblasts, brain, liver, and spleen of this patient revealed glucosylceramide beta-glucosidase (EC 3.2.1.45, glucocerebrosidase) activity about 10% of controls, and well in the range found in samples from Gaucher disease patients [24].

Gene context of Gaucher Disease

• To develop additional models of Gaucher disease and to test in vivo effects of saposin deficiencies, mice expressing low levels (4--45% of wild type) of prosaposin and saposins (PS-NA) were backcrossed into mice with specific point mutations (V394L/V394L or D409H/D409H) of GCase [25].
• Genetic fine localization of the beta-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease [26].
• The structural organization of the THBS3 gene is of interest because of its close proximity to that of metaxin, with which it shares a common promoter sequence, and to the gene encoding glucocerebrosidase, a deficiency in which causes Gaucher disease [27].
• High concentrations of IL-6 in the serum of patients with Gaucher's disease may thus reflect the development of the bone lesions commonly associated with this disorder [28].
• Pro-inflammatory cytokines and the pathogenesis of Gaucher's disease: increased release of interleukin-6 and interleukin-10 [28].

Analytical, diagnostic and therapeutic context of Gaucher Disease

• The ability to select for expression of GC with natural product drugs after introduction of the pHaMCG retroviral vector may be useful in gene therapy strategies for Gaucher disease [29].
• One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS [30].
• Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease [31].
• Human acid beta-glucosidase: Northern blot and S1 nuclease analysis of mRNA from HeLa cells and normal and Gaucher disease fibroblasts [32].
• Analyses of catalytic activity and inhibitor binding of human acid beta-glucosidase by site-directed mutagenesis. Identification of residues critical to catalysis and evidence for causality of two Ashkenazi Jewish Gaucher disease type 1 mutations [33].

References