Disease relevance of Gba

• A targeted mutation (A-->G in exon 9) was introduced into GC by homologous recombination in embryonic stem cells to establish a mouse model for a mild form of Gaucher disease [1].
• Gaucher disease is a common lysosomal storage disease caused by a defect of acid beta-glucosidase (GCase) [2].
• Absolute levels of human GC RNA and protein increased with increased copy numbers of provirus in the clones [3].
• Gaucher disease, the most common of the sphingolipidoses, results from the inherited deficiency of the enzyme glucocerebrosidase (EC 3.2.1.45) [4].
• Glucocerebrosidase cDNA and the neomycin-resistance gene (neo) were cloned into a retrovirus vector [5].

Psychiatry related information on Gba

• This unique case confirms the essential role of glucocerebrosidase in human development and, like the null allele Gaucher mouse, demonstrates the lethality of a homozygous null mutation [6].

High impact information on Gba

• Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene [7].
• Mice homozygous for this mutation have less than 4% of normal glucocerebrosidase activity, die within twenty-four hours of birth and store glucocerebroside in lysosomes of cells of the reticuloendothelial system [7].
• We conclude that MZ B cells are heterogeneous, comprising cells for both early AFC response and GC/memory pathway against TD antigens [8].
• We have developed adult mice carrying the Gaucher disease L444P point mutation in the glucocerebrosidase (Gba) gene and exhibiting a partial enzyme deficiency [9].
• Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage [9].

Chemical compound and disease context of Gba

• The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid beta-glucosidase (hGCase) transgenic system [10].
• Gaucher disease, the most common lysosomal storage disease, is caused by a deficiency of glucocerebrosidase resulting in the impairment of glucosylceramide degradation [9].
• 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].
• The outermost layer of Mycobacterium tuberculosis is composed primarily of two polysaccharides, glucan (GC) and arabinomannan [12].
• 3. Injection of phenylhydrazine produced hemolysis and spleen enlargement, with concomitant increases in specific activities of glucocerebrosidase and aryl glucosidase in liver and spleen (but not in kidney) [13].

Biological context of Gba

• Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease [1].
• Turning off hGCase expression with dietary DOX led to reaccumulation of storage cells and of GC in liver, lung, and spleen, and macrophage activation in those tissues [10].
• In the lysosomal sphingolipid degradation pathway, acid beta-glucosidase (GCase) requires saposin C for optimal in vitro and in vivo hydrolysis of glucocerebroside [14].
• Gaucher disease mouse models: point mutations at the acid beta-glucosidase locus combined with low-level prosaposin expression lead to disease variants [2].
• We mapped the genetic locus for glucocerebrosidase to mouse chromosome 3, at a position 7.6 +/- 3.2 centimorgans from the locus for the beta subunit of nerve growth factor [15].

Anatomical context of Gba

• Loading saposin C to human PS-/- fibroblasts resulted in an enhancement of GCase protein and in vitro activity [14].
• In contrast to PS-NA mice, the 4L/PS-NA and 9H/PS-NA mice displayed large numbers of engorged macrophages and nearly exclusive glucosylceramide (GC) accumulation in the liver, lung, spleen, thymus, and brain [2].
• Glucocerebrosidase therefore appears necessary for the generation of membranes of sufficient functional competence for epidermal barrier function [16].
• Isolation of a GC-rich cDNA identifying mRNA present in human epidermis and modulated by calcium and retinoic acid in cultured keratinocytes. Homology with murine loricrin mRNA [17].
• The glucocerebrosidase activity produced from translation products initiated at either ATG is found predominantly in the lysosomes [18].

Associations of Gba with chemical compounds

• A phosphoglycerate kinase-neomycin gene cassette was also inserted into the 3'-flanking region of GC as a selectable marker, at a site later identified as the terminal exon of metaxin [1].
• The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice [10].
• Treatment of PS-/- cells with leupeptin, an inhibitor of cysteine proteases, led to significant increases (approximately 2-fold) in GCase protein and in vitro activity [14].
• Gaucher and BrCBE-treated mice showed < 1% and < 5% of normal epidermal glucocerebrosidase activity, respectively, and the epidermis/SC of Gaucher mice demonstrated elevated glucosylceramide (5- to 10-fold), with diminished ceramide content [16].
• When conduritol-B-epoxide, a specific inhibitor of beta-glucocerebrosidase, was added to the culture medium, the synthesis of acylceramide was significantly suppressed in concert with a significant increase in acylglucosylceramide [19].

Other interactions of Gba

• Upon induction with IL-6 of the seven transduced clones to the macrophage phenotype, there was no significant change, overall, in RNA levels but some increase in human GC protein levels could be detected [3].
• These abnormalities were attributable to a decrease in beta-glucocerebrosidase (beta-GlcCer'ase) and acidic sphingomyelinase (aSMase) catalytic activity and enzyme degradation consequent to a pH-induced sustained serine protease (SP) activity [20].
• 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 [21].
• We have investigated the mRNA amounts of six lysosomal proteins (beta-hexosaminidase alpha- and beta-subunit, sphingolipid activator protein precursor, GM2 activator protein, lysosomal sialidase, beta-glucocerebrosidase) involved in the degradation of glycosphingolipids [22].
• Expression of the human multidrug resistance and glucocerebrosidase cDNAs from adeno-associated vectors: efficient promoter activity of AAV sequences and in vivo delivery via liposomes [23].

Analytical, diagnostic and therapeutic context of Gba

• Compared with that in wild-type cells (t(1/2) >24 h), the GCase protein in the PS-/- cells had a faster disappearance rate (t(1/2) approximately 1 h in mouse and approximately 8 h in human) as determined by metabolic labeling and immunoprecipitation with anti-GCase antibodies [14].
• In situ hybridization of a radiolabeled human glucocerebrosidase cDNA to high resolution human chromosomes demonstrated that a single locus encoding glucocerebrosidase is on 1q21, adjacent to a region of chromosome 1 (1qh) abundant in structural heteromorphisms [24].
• Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease [24].
• In this study, Glc-sph levels were measured using HPLC in tissues from mice with type 2 Gaucher disease created with a null glucocerebrosidase allele [4].
• Promoter activity was functionally assessed by ligation of a 2 kb glucocerebrosidase fragment to the protein coding segment of a bacterial neomycin resistance gene [25].

References