Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wiskott-Aldrich syndrome (WAS) arises from defects of the X-chromosome gene WASP. Severe platelet defects, thrombocytopenia with small platelets, are a hallmark of the disease, but clinical immunodeficiency based in lymphocyte dysfunction varies from negligible to life threatening among WAS patients. To address the connection between WASP mutations and clinical outcomes, we generated and characterized a panel of patient B cell lines. Three cell lines from patients with exon 2 missense mutations and mild immune dysfunction were found to express substantial levels of WASP mRNA and protein. On the other hand, 8 of 10 cell lines from patients with moderate or severe immune dysfunction lack detectable WASP protein. The findings suggest that the clinical variability of the WAS can partially be explained by the level of WASP protein in the patient's cells.
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PMID:Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients. 912 58

CGD is a rare inherited immunodeficiency syndrome, caused by the phagocytes' inability to produce (sufficient) reactive oxygen metabolites. This dysfunction is due to a defect in the NADPH oxidase, the enzyme responsible for the production of superoxide. It is composed of several subunits, two of which, gp91phox and p22phox, form the membrane-bound cytochrome b558, while its three cytosolic components, p47phox, p67phox and p40phox, have to translocate to the membrane upon activation. This is a tightly and intricately controlled process that involves, among others, several low-molecular weight GTP-binding proteins. Gp91phox is encoded on the X-chromosome and p22phox, p47phox and p67phox on different autosomal chromosomes, and a defect in one of these components leads to CGD. This explains the variable mode of inheritance seen in this syndrome. Clinically CGD manifests itself typically already at a very young age with recurrent and serious infections, most often caused by catalase-positive pathogens. Modern treatment options, including prophylaxis with trimethoprim-sulfamethoxazole and rIFN-gamma as well as early and aggressive anti-infection therapy, have improved the prognosis of this disease dramatically. CGD, as a very well-characterized inherited affection of the hematopoietic stem cells, is predestined to be among the first diseases to profit from the advances in cutting-edge therapeutics, such as gene therapy and in utero stem cell transplantation.
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PMID:The molecular basis of chronic granulomatous disease. 961 66

The Wiskott-Aldrich syndrome (WAS) is a severe disease of platelets (small size, thrombocytopenia) and lymphocytes (immunodeficiency) arising from mutations of the X-chromosome gene WASP. Because of the prominent role of cytoskeletal abnormalities, particularly the paucity of surface microvilli, in the cellular pathology of this disease, blood cells from WAS patients were examined for moesin, a cytoskeletal linker protein that stabilizes cell surface microvilli, filopodia and lamellipodia. Comparison of patient and normal lymphocytes by immunofluorescence microscopy and immunoblotting showed normal levels and distribution of moesin in lymphocytes of WAS patients. In contrast, platelets from WAS patients stained only dimly for moesin relative to normal platelets. Quantitation by immunoblot revealed significantly decreased moesin levels in WAS patient platelets relative to normal platelets (63.5 +/- 4.9% of normal levels, n = 8, P < 0.0001). A novel reaction of normal platelets was discovered that may play a role in the depletion of moesin in patient platelets, namely the cleavage of moesin as a late event in platelet activation in response to certain platelet agonists.
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PMID:The cytoskeletal linker protein moesin: decreased levels in Wiskott-Aldrich syndrome platelets and identification of a cleavage pathway in normal platelets. 1044 90

Bruton's tyrosine kinase (Btk) is considered an essential signal transducer in B-cells. Mutational defects are associated with a severe immunodeficiency syndrome, X-chromosome linked agammaglobulinemia (XLA). Here we show by coimmunoprecipitation that a member of the protein kinase C (PKC) family, PKCmu, is constitutively associated with Btk. Neither antigen receptor (Ig) crosslinking nor stimulation of B-cells with phorbol ester or H(2)O(2) affected Btk/PKCmu interaction. GST precipitation analysis revealed association of the Btk pleckstrin/Tec homology domain with PKCmu. Transient overexpression of PKCmu deletion mutants as well as expression of selected PKCmu domains in 293T cells revealed that both the kinase domain and the regulatory C1 region are independently capable of binding to the Btk PH-TH domain. These data show the existence of a PKCmu/Btk complex in vivo and identify two PKCmu domains that participate in Btk interaction.
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PMID:Bruton's tyrosine kinase (Btk) associates with protein kinase C mu. 1056 98

Wiskott-Aldrich syndrome, an inherited blood cell disorder due to mutations of the X-chromosome gene WASP (Wiskott-Aldrich syndrome protein), was characterized originally by thrombocytopenia, immunodeficiency, and eczema. Whereas platelet dysfunction is severe and consistent, immune defects are clinically variable, ranging from negligible to life threatening. To understand this heterogeneity, we quantified WASP in PBMC and platelets, and also in neutrophils, of patients with diverse mutations. A surprisingly complex pattern of WASP expression found for lymphoid cells formed the basis for dividing the patient mutations into four groups. Group A have low WASP levels in PBMC and higher levels in EBV cell lines, as well as near normal WASP RNA levels (7 patients, most with mild disease), suggesting that group A WASP molecules are hypersusceptible to proteolysis. Group B have low WASP levels in PBMC and EBV cells and similar low RNA levels (2 patients, moderate disease). Group C have discordant expression: WASP-positive peripheral T cells and WASP-negative peripheral B cells and EBV cell lines (9 patients, variable disease severity). Noteworthy among group C kindred are several instances of B cell lymphomas. In group D, PBMC and EBV cell lines are WASP negative (7 patients, severe disease). In contrast to the complex lymphoid cell expression patterns, all patient platelets examined were WASP negative (18 diverse patients). WASP absence in platelets provides an apparent molecular explanation for the universally severe platelet dysfunction in this disease, and the cumulative lymphoid cell findings suggest that WASP levels play a substantial role in determining immune outcome.
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PMID:WASP levels in platelets and lymphocytes of wiskott-aldrich syndrome patients correlate with cell dysfunction. 1057 Mar 26

Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder, is characterized by progressive T-cell immunodeficiency. Laboratory findings generally demonstrate reduced response to T-cell mitogens, markedly decreased serum concentration of IgM, and thrombocytopenia with small platelet volume. Allogeneic HLA-matched sibling bone marrow transplantation (BMT) can correct this disorder. We report the usefulness of X-linked polymorphic loci to detect X-allele gene tracking among WAS siblings and chimerism between a pre- and post-allogeneic matched sibling peripheral blood stem cell transplantation (PBSCT). A 3 1/2 year old boy with clinical and laboratory findings consistent with WAS underwent allogeneic matched sibling PBSCT. We used BclI restriction fragment length polymorphism (RFLP) of intron 18 of factor VII gene and MseI RFLP of the 5' flanking region of factor IX gene to detect X-allele gene tracking among siblings and family members and chimerism in patients between pre-and post-allogeneic matched sibling PBSCT. We were able to demonstrate that determination of BclI and MseI RFLP can be employed to recognize the difference in X-allele genes between the recipient and donor for allogeneic matched sibling PBSCT. The authors also were able to demonstrate that these polymorphic loci can detect full chimerism of donor hematopoietic cells in recipient blood after allogeneic PBSCT. This finding was correlated with improvement of post-PBSCT clinical and laboratory findings. BclI and MseI RFLP associated with X-chromosome can effectively track X-allele, detect carrier state, and demonstrate the different X-allele among male siblings, and chimerism of hematopoietic cells between donors and recipients in a setting of allogeneic matched sibling BMT or PBSCT for X-linked hereditary diseases such as Wiskott-Aldrich syndrome.
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PMID:The usefulness of X-linked polymorphic loci as gene markers to track X allele and chimerism in a post-allogeneic peripheral blood stem cell transplant patient with Wiskott-Aldrich syndrome. 1146 Sep 39

X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency caused by mutations in the gene coding for Bruton's tyrosine kinase (Btk) and is characterized by an arrest of B-cell development. We analysed Btk protein expression in platelets using flow cytometry and found that normal platelets express large amounts of Btk. Assessment of affected males from 45 unrelated XLA families revealed that platelets of the majority of the patients (37 out of 45 families) had decreased or absent Btk expression, and that platelets from carrier females of these families had both normal and mutated Btk expression, indicating that megakaryocytes in XLA carriers undergo random X-chromosome inactivation. These observations demonstrate that Btk is not crucial for maturation of megakaryocytes and the production of platelets. No correlation between Btk expression in platelets and clinical phenotype was observed in this study. Flow cytometric evaluation using platelets is a simple and rapid method to test Btk expression. It may be used as a screening test for XLA and for carrier detection, followed, if necessary, by more expensive mutation analyses.
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PMID:Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females. 1147 59

Mutations of WASP (Wiskott-Aldrich syndrome protein) underlie the severe immunodeficiency/platelet disorder Wiskott-Aldrich syndrome (WAS) and its milder variant X-linked thrombocytopenia (XLT). The affected gene, a 12-exon structure on the X-chromosome, is expressed exclusively in blood cells. The encoded product WASP is a 502-amino-acid scaffolding protein that functions in stimulus-induced nucleation of actin filaments to form dynamic cell surface projections. To date, more than 150 mutations have been identified in 300 WAS/XLT kindred worldwide, generally through methodologies that include sophisticated exon screening steps such as single-strand conformation analysis. We report here a simpler protocol, which was designed for use in clinical settings to identify the mutations of newly diagnosed patients. The approach relies on directly sequencing amplified exons according to a staggered schedule based on statistical evaluation of previous cases. In a 2 1/2-year trial, samples from 28 consecutive patients were analyzed; these included 3 "blindly labeled" previously studied cases. The mutations that were identified include a broad spectrum (8 missense, 3 nonsense, 5 splice site mutations, 11 small insertion/deletions, 1 large deletion) and were broadly distributed (in 10 of the 12 exons). All mutations were verified and no discrepancies were encountered. Per patient, a mean of six DNA sequencing reactions and 6-7 h of staff effort sufficed for mutation identification and verification, indicating that the protocol is cost-effective. This cumulative experience demonstrates the suitability, reliability, and versatility of the new protocol.
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PMID:A novel protocol to identify mutations in patients with wiskott-Aldrich syndrome. 1236 83

Wiskott-Aldrich syndrome (WAS), an inherited blood cell disorder due to mutations of the X-chromosome gene WASP (Wiskott-Aldrich Syndrome Protein), was characterized originally by thrombocytopenia, immunodeficiency and eczema. Whereas platelet dysfunction is severe and consistent, immune defects are clinically variable, ranging from negligible to life-threatening. To understand this heterogeneity, WASP was quantified in peripheral blood mononuclear cells of patients with diverse mutations. In this study we assessed the relationship between the mutation, protein expression and phenotype in WAS patients. The majority of the patients with missense mutations exhibited mild phenotype, whereas patients with premature stop codon were in most cases severe. We designed a one-step approach intended for use in identifying mutations in samples from newly diagnosed patients. The approach relies on direct sequencing of amplified exon regions in a staggered schedule that was based on the mutation distribution frequency in previous cases. The method proved to be fast and reliable. Definitive mutation information was generated for each patient studied.
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PMID:Regulation of Anti-Tumor Activity Using Monoclonal Antibodies to Alpha-Fetoprotein Receptor and after Immunization with This Protein. 1268 25

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by immunodeficiency, eczema, and thrombocytopenia with small platelets. The phenotype of affected males is usually severe, although female carriers of the disorder have no clinical signs of the genetic defect. This is explained by the preferential selection of the normal, nonmutated X-chromosome, as the active allele in hematopoietic cells. In the present article we describe a female case of WAS, with a G-to-A transition in the WASP gene at nucleotide 291. She displays mild thrombocytopenia, with both normal and small-sized platelets. A methylation analysis of the HUMARA gene showed a nonrandom X-chromosome inactivation pattern in which the X-chromosome carrying the normal WASP gene was preferentially inactivated, leaving the mutant gene active. Thus, our results suggest that skewed X-inactivation, favoring the WASP-mutated allele, is the mechanism underlying the WAS phenotype of this girl. Moreover the results alert us to the fact that particular females, with a family history of WAS, may develop certain signs of the disease.
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PMID:Wiskott-Aldrich syndrome in a female with skewed X-chromosome inactivation. 1463 48


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