Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFalpha, M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFalpha were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.
Blood Cells Mol Dis 1997 Aug
PMID:Elevated levels of M-CSF, sCD14 and IL8 in type 1 Gaucher disease. 923 58

Gaucher disease is an inherited sphingolipidosis resulting from deficient glucocerebrosidase activity. Three clinical forms of Gaucher disease have been described: type 1 as non-neuronopathic, type 2 as acute neuronopathic, and type 3 as subacute neuronopathic. We recently identified a rare mutation (G-->A at glucocerebrosidase cDNA nucleotide position 1604) [Choy et al., 1994a, Am J Med Genet 51:156-160] and a novel mutation (T-->G at glucocerebrosidase cDNA nucleotide position 1366) in two type 1 Gaucher patients by sequence analysis of the entire glucocerebrosidase coding region [Choy et al., 1994a, 1994b, Hum Mol Genet 3:821-823]. To demonstrate that these are deleterious and not neutral mutations, we cloned the full-length glucocerebrosidase cDNA of patients and of a normal control in the plasmid vector pAcUW1, recombined the human gene into the Baculovirus genome downstream of its polyhedron p10 promoter, and expressed the inserted gene in cultured cells of Spodoptera frugiperda transfected by recombinant Baculovirus. The levels of residual glucocerebrosidase activity determined in transfected cells with the Gaucher G1604A and T1366G alleles are 6.9% and 2.9% of that expressed by the normal allele (normal = 352.0 nmol/hr/mg protein or 100%). By comparison, the enzyme-specific activity expressed in transfected cells by 2 known Gaucher alleles, A1226G and T1448C, that are prevalent in type 1 and type 2 Gaucher disease are 23.4% and 3.3% of normal. No endogeneous glucocerebrosidase activity was detected in cultured cells transfected by either the wild-type Baculovirus or Baculovirus with the pAcUW1 plasmid vector without the glucocerebrosidase cDNA insert. These findings show that the Baculovirus expression system in cultured Spodoptera frugiperda cells is a suitable system for the functional expression and characterization of the normal and mutant glucocerebrosidase alleles. Moreover, the use of this expression system demonstrates that the G1604A and T1366G mutations are both deleterious mutations resulting in profoundly deficient glucocerebrosidase activity and subsequent Gaucher disease.
 ...
PMID:Gaucher disease: functional expression of the normal glucocerebrosidase and Gaucher T1366G and G1604A alleles in Baculovirus-transfected Spodoptera frugiperda cells. 924 Jul 41

The inherited deficiency of glucocerebrosidase results in a group of sphingolipid storage disorders referred to collectively as Gaucher disease. Study of the biochemistry and cell biology of glucocerebrosidase has made possible an effective enzyme replacement therapy for the disease. Definition of the molecular genetics of glucocerebrosidase has improved diagnostic capabilities and presents the exciting possibility of a cure through gene therapy.
Cytokines Mol Ther 1995 Sep
PMID:Molecular biology of glucocerebrosidase and the treatment of Gaucher disease. 938 72

Gene fusions can be employed to ensure concomitant expression of two different proteins under the same transcriptional control elements. We have synthesized a retroviral expression vector (pHaMG1) containing a human multidrug resistance (MDR1)-glucocerebrosidase (GC) chimeric gene inserted between the long terminal repeats of the Harvey murine sarcoma virus. When introduced into psi-CRE mouse fibroblasts, pHaMG1 conferred the drug-selectable multidrug resistance phenotype, and drug-resistant clones produced active human GC of about 60 kDa. Percoll gradient fractionation of homogenates prepared from transfectants confirmed correct targeting of P-glycoprotein to the plasma membrane and of GC to lysosomes. Although this construction was designed as a translational fusion of the MDR1 gene product, P-glycoprotein, and human GC, no evidence for a fusion protein was found in transfected cells, and an analysis of the RNAs transcribed from the integrated pHaMG1 retroviral vector suggests that either P-glycoprotein and GC are translated from one mRNA and rapidly processed into two proteins or they are translated separately from different mRNAs. These results reveal the feasibility of using fusion genes, which are smaller than alternative constructions with two promoters or with an internal ribosome entry site, for coexpression of selectable and nonselectable cDNAs in retroviral vectors.
Cytokines Mol Ther 1996 Mar
PMID:Construction and characterization of a selectable multidrug resistance-glucocerebrosidase fusion gene. 938 89

Gaucher disease, the most common glycolipid storage disease, is caused by glucocerebrosidase deficiency, resulting in accumulation of glucocerebrosides within the macrophages of the reticuloendothelial system. The disease is characterized by great phenotypic heterogeneity, which can be explained only in part by the various mutations in the glucocerebrosidase gene, and by the amount of storage material in affected organs and tissues. Therefore, it has been postulated that some of the biochemical and clinical features may be related to the fact that "Gaucher" cells, as activated macrophages, express and release cytokines such as IL-1beta, IL-8, IL-6 and TNF-alpha which play a role in different physiological processes. In the present study, cytokine mRNA expression was measured in monocytes isolated from Gaucher patients and from healthy controls, using RT-PCR methodology with semiquantitative analysis. We found significantly increased expression of IL-1beta mRNA, as well as a trend to elevated TNF-alpha mRNA in Gaucher patients relative to healthy individuals. There were no statistically significant differences between Gaucher disease patients and controls with respect to two other tested cytokines (IL-6 and IL-8).
Blood Cells Mol Dis 1997 Dec
PMID:Cytokine mRNA in Gaucher disease. 944 53

A new polymorphism, in intron 7 of glucocerebrosidase gene, has been identified in Gaucher Disease patients. It seems to appear only in Pv1.1- alleles bearing the N370S mutation. This new sub-haplotype was only identified in Portuguese patients, of origins spanning all of the Portuguese continental territory. This finding indicates that, in the Portuguese, mutation N370S has existed in the context of two slightly different haplotypes and thus must be relatively ancient.
Blood Cells Mol Dis 1997 Dec
PMID:Distinct haplotype in non-Ashkenazi Gaucher patients with N370S mutation. 944 56

Gaucher disease is caused by a deficiency of glucocerebrosidase, resulting in hepatosplenomegaly, pancytopenia, growth retardation and skeletal involvement. We analyzed data on genotype and key clinical parameters in 35 Japanese patients with Gaucher disease type 1. Our data demonstrated that over 60% of patients had onset of Gaucher disease signs/symptoms at less than 5 years. Sixty percent and 46% of evaluable patients were splenectomized and developed severe bone involvement, respectively. Within mean follow-up periods of 8 years and 4 months, mean relative height and weight, severity score index and platelet count all worsened to a highly significant degree. These data suggest that type 1 Gaucher disease tends to be severe and progressive in Japanese patients, most of whom would be suitable for treatment and might indeed require earlier and more aggressive therapy.
Blood Cells Mol Dis 1998 Mar
PMID:Type 1 Gaucher disease: phenotypic expression and natural history in Japanese patients. 954 79

Both the L-type pyruvate kinase gene (PKLR) and glucocerebrosidase (GBA) gene are on band q21 of chromosome 1 in humans. Two overlapping P1 bacteriophage clones containing PKLR and GBA were identified and mapped, defining the locations of these two genes as well as those of the GBA pseudogene (psi GBA) metaxin (MTX), the MTX pseudogene (psi MTX), and thrombospondin 3 (THBS3). The distance between the 5' ends of GBA and PKLR was determined to be 71 kb. The direction of transcription PKLR gene was convergent to that of the GBA gene. All 195 Gaucher disease patients homozygous for the 1226G mutation, representing 390 chromosomes with the 1226G mutation, had a PvuII -/- GBA haplotype and a C/C at nt 1705 of the PKLR gene (-/- haplotype). All 56 Gaucher disease patients who were 1226G/84GG compound heterozygotes manifested a -/+ GBA haplotype and 55 of 56 patients were -/+ at PKLR nt 1705. Only 1 patient with 1226G/84GG genotype showed a crossover with the PKLR polymorphism, with a -/- haplotype at nt 1705. Similarly, 9 patients deficient in pyruvate kinase with the PKLR 1529A/1529A genotype were all found to have the same -/- GBA haplotype.
Hematopathol Mol Hematol 1998
PMID:Structure and linkage relationships of the region containing the human L-type pyruvate kinase (PKLR) and glucocerebrosidase (GBA) genes. 960 55

Gaucher disease, the deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45), is frequently encountered in the Ashkenazi Jewish population. Carrier screening for Gaucher disease by enzyme analysis performed during a routine pregnancy indicated that both Ashkenazi parents were carriers. Screening for four common Gaucher mutations was subsequently performed on fetal and parental DNA. None of the common Ashkenazi mutations were identified. However, when exons 9-11 were amplified and digested with NciI to detect the L444P mutation, it appeared that the mother and the fetus had an unusual allele and that the expected paternal allele was not present. When the fetal amniocytes were found to have less than 2% of the normal glucocerebrosidase activity and a fetal sonogram revealed hydrops fetalis, the pregnancy was terminated. The diagnosis of severe type 2 Gaucher disease was confirmed at autopsy. Ultrastructural studies of epidermis from the fetus revealed the characteristic disruption of lamellar bilayers, diagnostic for type 2 Gaucher disease. In subsequent studies of the fetal DNA, long-template polymerase chain reaction amplification revealed one appropriately sized band (approximately 6.5 kb) and one smaller (approximately 5.2 kb) band. Sequencing of the approximately 5.2-kb fragment identified a novel fusion allele resulting from recombination between the glucocerebrosidase gene and its pseudogene beginning in intron 3. This fusion allele was inherited from the father. The result was confirmed by Southern blot analysis using the enzyme S8tII. Sequencing of the 6.5-kb fragment identified a previously described, although rare, T-to-G splice junction mutation in intron 10 of the maternal allele, which introduced an NciI site. The couple had a subsequent pregnancy which was also found to be affected. This case study identifies a novel recombinant allele and an unusual splice junction mutation, and demonstrates that even in the Ashkenazi population, screening for common mutations may not accurately identify the most severe forms of the disease.
Mol Genet Metab 1998 Apr
PMID:Type 2 Gaucher disease with hydrops fetalis in an Ashkenazi Jewish family resulting from a novel recombinant allele and a rare splice junction mutation in the glucocerebrosidase locus. 963 96

It is suggested that corticotrophin-releasing hormone (CRH) is involved in parturition. We have previously reported the presence of the CRH receptor subtype 1 (CRH R1) in human uterine myocytes. The aim of the present study was to investigate whether expression of the CRH R1 in myometrial tissue changes in pregnancy and labour. We used a quantitative competitive PCR method to measure the mRNA levels of this receptor in non-pregnant and in term pregnant myometrium before and at different stages of labour. The levels of mRNA for the housekeeping gene for glucocerebrosidase (GCB) were also determined. The results were expressed as a ratio of CRH R1 and GCB mRNA levels. We have found that in pregnancy the CRH R1 is down-regulated from a ratio of 0.093+/-0.011 in non-pregnant myometrium to 0.012+/-0.005 (P<0.001) in term non-labouring myometrium. No significant changes were observed in the CRH R1:GCB ratio in tissues sampled within 13 h (0.013+/-0.004) from the start of labour. In summary, normalised levels of CRH R1 are down-regulated in pregnancy and do not change during labour. We speculate that our results do not support a direct role for the CRH R1 receptor in myometrial stimulation.
J Mol Endocrinol 1998 Oct
PMID:Levels of corticotrophin-releasing hormone receptor subtype 1 mRNA in pregnancy and during labour in human myometrium measured by quantitative competitive PCR. 980 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>