Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency affecting B lymphocytes, T lymphocytes, and platelets. Previous studies on lymphocytes from WAS patients have revealed that leu-kosialin (CD43), a cell-surface glycoprotein bearing approximately 90 O-linked oligosaccharide chains, shows an aberrant electrophoretic mobility. To determine whether this finding reflects a different pattern of O-linked glycosylation in WAS cells, we have compared healthy individuals and WAS patients with respect to glycosyltransferase activities in T lymphocytes, platelets, and Epstein-Barr virus (EBV)-immortalized B cell lines. Stimulation of peripheral T cells from normal individuals in vitro with anti-CD3 antibodies and interleukin-2 was associated with a 3-fold increase in UDP-GlcNAc:Gal beta 3GalNAc-R (GlcNAc to GalNAc) beta 6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T) from 0.8 to 2.2 nmol/mg/h. In contrast, peripheral T lymphocytes from WAS patients showed an inversion of this phenotype with high core 2 GlcNAc-T activity in unstimulated cells (2.3 nmol/mg/h) and a 2-3-fold decrease in activity following stimulation. Core 2 GlcNAc-T activity was also three times higher in platelets from WAS patients than in normal platelets. Glycosyltransferase activities were measured in immortalized B cell lines established from WAS and normal subjects by infection with EBV. Core 2 GlcNAc-T was less than 0.4 nmol/mg/h in WAS EBV-B cell lines compared to 2.4 nmol/mg/h in EBV-B cell lines from healthy individuals, In contrast, CMP-SA:SA alpha 2-3Gal beta 1-3GalNAc-R (where SA represents sialyl (sialic acid to GalNAc) alpha 6-sialyltransferase II activity was 2.0 nmol/mg/h in the WAS EBV-B cell and less than .01 nmol/mg/h in EBV-B cell lines derived from normal subjects. Eleven other glycosyltransferase activities were measured and found to be similar in EBV-B cell lines from WAS and normal individuals. Polylactosamine sequences were much reduced in the O-linked oligosaccharides of CD43 from WAS EBV-B cells consistent with decreased core 2 GlcNAc-T activity and expression of core 1 oligosaccharides in the cells. In conclusion, B cells, T cells, and platelets in WAS patients show abnormal expression of two developmentally regulated glycosyltransferases, consistent with the idea that the WAS immunodeficiency is due to a failure of normal lymphocyte maturation.
 ...
PMID:Aberrant O-linked oligosaccharide biosynthesis in lymphocytes and platelets from patients with the Wiskott-Aldrich syndrome. 200 80

UDP-GlcNAc:Gal beta 3GalNAc-R (GlcNAc to GalNAc) beta 1-6-N-acetylglucosaminyltransferase (i.e. core 2 GlcNAc-T) of the O-linked oligosaccharide pathway is developmentally regulated in human T cells, and changes in its activity have been associated with malignancies and the Wiskott-Aldrich immunodeficiency syndrome. Chinese hamster ovary (CHO) cells normally express low levels of core 2 GlcNAc-T activity (8-12 pmol/mg/h) which can be accurately measured with a two-step assay employing purified bovine beta 1-4Gal-T and high specific activity UDP-[3H]Gal to radiolabel the core 2 reaction product. CHO cells treated with 2 mM sodium butyrate for 24 h exhibited a 16-fold increase in core 2 GlcNAc-T activity, whereas several other differentiating agents including dimethyl sulfoxide, retinoic acid, phorbol ester, and cholera toxin had no effect on activity. The addition of butyrate, cholera toxin, or dimethyl sulfoxide to CHO cells slowed cell proliferation and induced changes in cell morphology characteristic of cell differentiation. Induction of core 2 GlcNAc-T by butyrate was blocked by actinomycin D and cycloheximide. Butyrate treatment also elevated cytosolic cAMP levels with a time course which paralleled, but preceded, induction of core 2 GlcNAc-T activity by approximately 8 h. The protein kinase inhibitors H-7 and H-8 blocked butyrate-dependent induction of enzyme activity, whereas the inactive analogue H1004 had no effect. Core 2 GlcNAc-T showed a change in Km for UDP-GlcNAc, from 0.50 mM in untreated cells to 4.54 mM in butyrate + cholera toxin treated CHO cells, but no changes in Km for the synthetic acceptor, Gal beta 1-3GalNAc alpha-para-nitrophenyl. Despite the 9-fold increase in Km for sugar nucleotide, Vmax/Km was 8.8-fold greater in treated compared with untreated cells. These observations suggest that in CHO cells induction of core 2 GlcNAc-T by butyrate treatment requires de novo gene transcription/translation, activation of protein kinase(s), and is associated with changes in the kinetic properties of the enzyme.
 ...
PMID:Regulation of UDP-GlcNAc:Gal beta 1-3GalNAc-R beta 1-6-N-acetylglucosaminyltransferase (GlcNAc to GalNAc) in Chinese hamster ovary cells. 838 71

The Wiskott-Aldrich syndrome (WAS) is an uncommon X-linked recessive disease characterized by thrombocytopenia, eczema and immunodeficiency. The biochemical defect of this disorder primarily affects cells derived from bone marrow. To understand better the molecular mechanisms underlying this disease and to evaluate the possibility of correcting the genetic defects in hematopoietic cells, a Moloney murine leukemia virus (MoMLV)- based retroviral vector carrying a functional Wiskott-Aldrich syndrome protein (WASp) cDNA driven by an SV40 promoter (LNS-WASp) was constructed. A packaging cell line containing this vector produced a stable level of WAS protein and maintained a high titer of viral output. Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines (B-LCL) from WAS patients, which lack expression of the WAS protein, were transduced by the LNS-WASp retroviral vector and showed expression of WASp by Western blot. Analysis of the O-glycan pattern on cell surface glycoproteins from WAS patients' B-LCL showed an altered glycosylation pattern, due to increased activity of beta-1, 6-N-acetylglucosaminyltransferase (C2GnT). Transduction by the retroviral vector carrying the functional WASp cDNA partially restored the abnormal glycosylation pattern, and was accompanied by a decreasing C2GnT activity. These findings imply a functional linkage between the WAS protein and the expression of the glycosyltransferase involved in the O-glycosylation, and also suggest a potential gene therapy via transferring a functional WASp cDNA into hematopoietic cells for Wiskott-Aldrich syndrome. Gene Therapy (2000) 7, 314-320.
 ...
PMID:Expression of human Wiskott-Aldrich syndrome protein in patients' cells leads to partial correction of a phenotypic abnormality of cell surface glycoproteins. 1069 12