Disease relevance of GBA

• Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA) [1].
• Mutations in the glucocerebrosidase (GBA) and prosaposin (PSAP) genes are responsible for Gaucher disease, the most prevalent sphingolipidosis [2].
• Mutations in the human glucocerebrosidase gene (GBA) may lead to Gaucher disease-an autosomal recessive, lysosomal storage disease [3].
• An association between mutations in the glucocerebrosidase (GBA) gene and Parkinson disease (PD) was recently reported in Ashkenazi Jews [4].
• BACKGROUND: A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosidase gene (GBA), and parkinsonism [5].

Psychiatry related information on GBA

• To know if both tracers reacted in the same manner when brain cholinergic neurotransmission was activated, CBF and GC were measured in young normals (YN), aged normals (AN), and Alzheimer's Disease patients (AD) using positron emission tomography (PET), H2 15O, and 18F-FDG [6].
• Similar data on two cases of Huntington's disease showed no significant correlations, while 1 patient with Parkinson dementia showed a significant (negative) correlation only with Gluc [7].

High impact information on GBA

• A less costly regimen of alglucerase to treat Gaucher's disease [8].
• Alglucerase (Ceredase) provides effective enzyme-replacement treatment for patients with Gaucher's disease, but at the usually recommended dose of 60 U per kilogram of body weight every two weeks (130 U per kilogram per month), it costs $382,200 per year for a 70-kg patient [8].
• A severe neonatal type 2 variant who presented with collodion skin, ichthyosis, and a rapid neurodegenerative course had two novel acid beta-glucosidase alleles: a complex, maternally derived allele, E326K+L444P, and a paternally inherited nonsense mutation, E233X [9].
• Gaucher disease, the most prevalent lysosomal storage disease, occurs in three subtypes, all resulting from mutations in the acid beta-glucosidase gene [10].
• These mutations further expand the genetic heterogeneity in the lesions causing Gaucher disease types 1 and 2, and further delineate genotype/phenotype correlations and functional domains within the acid beta-glucosidase gene [10].

Chemical compound and disease context of GBA

• Gaucher disease types 1, 2, and 3: differential mutations of the acid beta-glucosidase active site identified with conduritol B epoxide derivatives and sphingosine [11].
• Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-beta-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide [12].
• Whether overexpressed from the MFG-GC retrovirus or the tetracycline transactivator system, there was a large discrepancy between the amounts of mRNA (>750-fold) and acid beta-glucosidase protein (approximately 6- to 14-fold) produced in mammalian cells [13].
• Previous studies have suggested that the yield of Streptococcus pneumoniae from respiratory secretions can be increased by using a 5% sheep blood agar plate supplemented with 5 microgram of gentamicin (GBA) per ml [14].
• 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 [15].

Biological context of GBA

• To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes [1].
• In conclusion, 12% of HALP subjects were found to carry mutations in apo A-I, LCAT, or GBA genes, which could explain this phenotype [16].
• Detailed haplotype phylogeny suggests that the chimpanzee GBA haplotype is not one of the two most frequent haplotypes [17].
• Two other SNPs in GBA were typed in three African populations [17].
• PKLR- GBA region shows almost complete linkage disequilibrium over 70 kb in a set of worldwide populations [17].

Anatomical context of GBA

• Somatic cell hybrid analysis and in situ hybridization experiments have localized the GBA gene to 1q21 and the PSAP gene to 10q21-q22 [2].
• Using a RAG X human fibroblast line with a mouse-human rearrangement of human chromosome 1, the locus for GBA was limited to the region 1p11 to 1qter [18].
• Using the polymerase chain reaction (PCR) with primers specific for the GC pseudogene, we found that all the human cell lines examined, HL-60, K-562, WI-38, HepG2 and HeLa, expressed a pseudogene transcript [19].
• Proteins associated with lysosomal membranes, acid beta-glucosidase, acetyl-coenzyme A:alpha-glucosaminide N-acetyltransferase, CD63/LIMP I, and h-lamp-2 were enriched approximately 300-fold as compared to the initial homogenate [20].
• The presence of creatine, guanidinopropionic acid (GPA) and guanidinobutyric acid (GBA) was demonstrated in red blood cells from uremic patients; they were found only in trace amounts in red blood cells of normal controls [21].

Associations of GBA with chemical compounds

• Three of these markers (D1S2777, D1S303, and D1S2140), as well as the gene encoding pyruvate kinase (PKLR), are contained in a single YAC clone together with the GBA gene [2].
• Human acid beta-glucosidase (D-glucosyl-N-acylsphingosine glucohydrolase, EC 3.2.1.45) cleaves the glucosidic bonds of glucosylceramide and synthetic beta-glucosides [22].
• Clinical and biochemical parameters of GC sensitivity were measured: weight, height, waist to hip ratio, glucose, insulin, total cholesterol, high-density lipoprotein, and C-reactive protein [23].
• Molecular analysis of the patients showed homozygosity for a novel mutation (C5390G) of the beta-glucocerebrosidase gene, resulting in the substitution of the arginine 353 with a glycine [24].
• A similar frequency of CpG dinucleotides was observed in GBA and in psGBA, and CpG pairs were mutated with the same high frequency in both regions [25].

Regulatory relationships of GBA

• Alglucerase induces a linear decline in immunoglobulin and beta 2-microglobulin levels [26].

Other interactions of GBA

• A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations [1].
• Our results show that six markers cosegregate with the GBA gene (Zmax = 8.73 at theta = 0.00 for marker D1S2714) and define a 3.2-cM interval between D1S305 and D1S2624 as the most probable location for the gene [2].
• There exists 16kb downstream from the functional GBA gene (chromosome 1q21) a highly homologous transcribed pseudogene (GBAP) with some sequence differences to GBA [3].
• The origin and endpoints of the duplication leading to the pseudogenes for GBA and MTX are now clearly established [27].
• Of these three genes, the gene most distal to GBA is a protein kinase (clk2) [27].

Analytical, diagnostic and therapeutic context of GBA

• The human enzyme was detected in mouse RAG cell-human fibroblast cell hybrids by a sensitive double antibody immunoprecipitation assay using a mouse antihuman GBA antibody [18].
• The GBA gene was initially scanned for nine previously described mutations by ASO hybridization or restriction analysis after PCR amplification [28].
• The structural gene for human acid beta-glucosidase (GBA) has been assigned to chromosome 1 using somatic cell hybridization techniques for gene mapping [18].
• These fusion proteins are shown by Western blotting to react with antibody to beta-glucocerebrosidase [29].
• Using site-directed mutagenesis, we constructed plasmids containing wild-type and several mutations in glucocerebrosidase (GBA) gene [30].

References