Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by eczema, thrombocytopenia, and profound immunodeficiency in affected males. While the etiology of the syndrome is currently unknown, abnormalities of CD43 have been described as a biochemical marker of the disease. Several investigators have demonstrated alterations in the expression of the CD43 surface antigen on WAS hematopoietic cells, noting either absence, decreased levels or changes in the characteristic molecular weight of the protein on the lymphocytes of affected patients. Biochemical studies have further indicated that glycosylating activity of specific enzymes which may post-translationally modify CD43 is altered in both T cells and Epstein-Barr-virus (EBV)-transformed B cells in WAS patients when compared to unaffected controls. Here we present data on cells derived from two males with a clinical diagnosis of WAS. Analysis of genomic DNA from the mothers of each of these patients (obligate carriers) showed a nonrandom X-chromosome inactivation pattern of nucleated blood cells, confirming the diagnosis of the X-linked syndrome. CD43 was characterized on peripheral blood lymphocytes and long-term EBV-transformed B cell lines, both to further analyze the molecular defects of WAS, as well as to attempt to generate a reproducible method for disease detection. Surprisingly, surface expression, molecular weight and two-dimensional gel analysis failed to demonstrated any reproducible differences in the CD43 expression, whether from disease or normal lymphocytes. Such results suggest possible heterogeneity of this syndrome.
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PMID:CD43 is expressed normally on Wiskott-Aldrich-derived lymphocytes. 133 89

The Wiskott-Aldrich syndrome (WAS) is a severe immunodeficiency and platelet deficiency disease arising from an X-linked defect. The disease is correctable by transplantation of hematopoietic stem cells, but the product of the defective gene is unidentified and the number of defects in patient blood cells is large. The current hurdle is the need to identify the early pathogenic event(s) that are the cause of other defects. As a step toward this goal, we have generated and examined a panel of interleukin 2-dependent allospecific T cell lines from peripheral lymphocytes of seven WAS patients and five normal individuals. WAS cell lines, like normal lines, undergo vigorous proliferation when challenged with specific allostimulant or with phorbol myristate acetate and ionomycin. Both normal and WAS T cell lines express cell surface molecules CD2, CD3, T cell receptor-alpha/beta, human histocompatibility leukocyte antigen class I, CD45 and CD11a, and varying ratios of CD4 and CD8, and are negative for natural killer cell and monocyte surface molecules. WAS T cell lines express CD43 (sialophorin/leukosialin) with molecular weight and in an amount comparable with normal T cell lines. WAS T cell lines thus do not express defects in CD43 (decreased amount, abnormal molecular weight), previously documented in WAS circulating lymphocytes. On the other hand, as detected by scanning electron microscopy, WAS cell lines exhibit severe morphological abnormalities, including decreased size and density of the microvillus surface projections. The morphological abnormalities of WAS T cell lines are similar to, or more extensive than, those previously reported for WAS peripheral lymphocytes, indicating that the generation of morphological (cytoarchitectural) defects is an early pathogenic event in this disease. The findings suggest that the gene that is defective in the WAS encodes a protein that normally functions to maintain or regulate the cytoskeletal structure of blood cells.
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PMID:T cell lines characterize events in the pathogenesis of the Wiskott-Aldrich syndrome. 151 49

The Wiskott-Aldrich syndrome (WAS) is an inherited disease involving defects of platelets (small size, severe thrombocytopenia due to accelerated destruction) and T lymphocytes (progressive immunodeficiency, lymphopenia). The best-characterized molecular defect is the deficiency and, in some cases, abnormal forms of the T-lymphocyte surface mucin molecule CD43; deficiency of the platelet surface mucin GPIb was observed previously in two of four patients. Neither of these defects is primary, since CD43 and GPIb are encoded by autosomal genes and the disease is X-linked. This study uses cellular biological approaches to explore the possibility that destruction of structurally defective WAS platelets, mimicked experimentally by sonication of normal platelets, plays a role by releasing protease and generating other cellular defects. We show that a protease of normal platelets, identified as Ca(2+)-dependent neutral protease (calpain), which is known to cleave platelet GPIb, also specifically cleaves CD43 on the surface of neighboring desialylated T lymphocytes. The identification of the CD43 cleaving protease was based on its requirement for Ca2+ and inhibition by leupeptin, but not by diisopropylfluorophosphate (DFP). The approximate site of CD43 cleavage was identified by the use of a rabbit antibody. Sensitivity of GPIb to calpain is shown to be sialylation-independent and that of CD43 to be sialylation-dependent, and these findings are explained in terms of molecular structures. These and previous findings are incorporated into a putative mechanism, which explains most of the defects in the WAS. The mechanism suggests that the primary defective molecule in the WAS is unlikely to be a surface glycoprotein, but rather a cytoplasmic molecule with a function in cytoskeletal interactions and/or calcium ion regulation and calpain activation.
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PMID:Effect of platelet calpain on normal T-lymphocyte CD43: hypothesis of events in the Wiskott-Aldrich syndrome. 155 70

Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott-Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.
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PMID:Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation. 199 98

The only molecular defect reported for the X-linked immunodeficiency Wiskott-Aldrich syndrome (WAS) is the abnormal electrophoretic behavior of the major T lymphocyte sialoglycoprotein CD43. Since the 70 to 80 O-linked carbohydrate chains of CD43 are known to influence markedly its electrophoretic mobility, we analyzed the structure and the biosynthesis of O-glycans of CD43 in lymphocytes from patients with WAS. Immunofluorescence analysis with the carbohydrate dependent anti-CD43 antibody T305 revealed that in 10 out of the 12 WAS patients tested increased numbers of T lymphocytes carry on CD43 an epitope which on normal lymphocytes is expressed only after activation. Other activation antigens were absent from WAS lymphocytes. Western blots of WAS cell lysates displayed a high molecular mass form of CD43 which reacted with the T305 antibody and which could be found on in vivo activated lymphocytes but was absent from normal unstimulated lymphocytes. To examine the O-glycan structures, carbohydrate labeled CD43 was immunoprecipitated and the released oligosaccharides identified. WAS lymphocyte CD43 was found to carry predominantly the branched structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4G1cNAc beta 1----6) GalNAcOH whereas normal lymphocytes carry the structure NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----6) GalNAcOH. Only after activation NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH becomes the principal oligosaccharide on CD43 from normal lymphocytes. Analyzing the six glycosyltransferases involved in the biosynthesis of these O-glycan structures it was found that in WAS lymphocytes high levels of beta 1----6 N-acetyl-glucosaminyl transferase are responsible for the expression of NeuNAc alpha 2----3Gal beta 1----3 (NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6) GalNAcOH on CD43. The gene responsible for WAS has not yet been identified but the results presented in this study suggest that the primary defect in WAS may affect a gene which is involved in the regulation of O-glycosylation.
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PMID:Altered O-glycan synthesis in lymphocytes from patients with Wiskott-Aldrich syndrome. 203 71

Detailed studies on the rare disorder X-linked thrombocytopenia showed that it resembles the Wiskott-Aldrich syndrome (WAS) in inheritance, clinical bleeding tendency, platelet morphology, marked thrombocytopenia and microplatelets. The calculated platelet mass was 5% of normal. Functional and biochemical studies indicated qualitatively normal aggregation and release mechanisms, whereas a moderate storage pool defect was present. The classical platelet membrane glycoproteins and lymphocyte sialophorin (CD 43) were normal. The reason for the bleeding tendency was concluded to be deficient hemostatic plug formation resulting from the low platelet mass and a moderate storage pool defect. The only clear distinction from WAS was the normal immunofunctional tests, the moderate tendency to infections and the absence of eczema. We therefore consider the trait as an attenuated form of WAS. That women are affected may indicate a particular variant.
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PMID:X-linked thrombocytopenia and thrombocytopathia: attenuated Wiskott-Aldrich syndrome. Functional and morphological studies of platelets and lymphocytes. 204 54

The Wiskott-Aldrich syndrome (WAS) is an X-linked immune deficiency disorder characterized clinically by both lymphocyte and platelet dysfunction. Studies of WAS T lymphocytes have revealed deficient or defective cell surface expression of the highly O-glycosylated leucocyte sialoglycoprotein CD43. To further elucidate the basis for, and functional relevance of, CD43 modifications on WAS lymphocytes, we have studied lymphocytes from two WAS patients with regard to membrane glycoprotein profile and mitogen-induced proliferative responses. CD43 was found to be either absent or altered in size on peripheral blood lymphocytes and lectin-stimulated T cells from both patients. Compared with control cells, the WAS lymphocytes displayed reduced, but measurable proliferative responses to lectins and neuraminidase/galactose oxidase, and virtually no response to periodate, a mitogenic agent which targets sialic acid residues on membrane glycoproteins such as CD43. Analysis of activities of three glycosyltransferases involved in O-glycosylation revealed marked reduction in the level of activity of UDP-N-acetylglucosamine: Gal beta 1-3GalNAc-R beta-1,6-N-acetylglucosamine (beta-1,6-GlcNAc) transferase in one WAS patient and no detectable activity of this enzyme in a second. beta-1,6-GlcNAc transferase activity has recently been shown to increase during T cell activation coincident with changes in the O-linked glycans on CD43. A selective reduction of this glycosyltransferase in WAS lymphocytes suggests that O-linked oligosaccharides may be important to the structure of membrane glycoproteins involved in lymphocyte activation.
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PMID:Altered expression of leucocyte sialoglycoprotein in Wiskott-Aldrich syndrome is associated with a specific defect in O-glycosylation. 280 29

The mAb L10 was used to determine the distribution and the function of sialophorin, the heavily glycosylated surface molecule that is deficient/defective in lymphocytes of patients with the X-linked immunodeficiency Wiskott-Aldrich syndrome. Dual-parameter FACS analysis indicated that sialophorin is expressed on CD4+ and CD8+ lymphocytes, on a subpopulation of peripheral blood B lymphocytes, on all thymocytes, and on a subpopulation of bone marrow cells. Functional studies demonstrated that L10 mAb stimulates the proliferation of peripheral blood T lymphocytes as measured by stimulation of [3H]thymidine incorporation. The time course and magnitude of increased [3H]thymidine incorporation by T lymphocytes in response to L10 mAb paralleled that induced by anti-CD3 mAb. Effective stimulation was dependent on the presence of monocytes and the Fc portion of L10 mAb. Stimulation of lymphocytes by L10, like stimulation by anti-CD3 mAb, involves increased expression of 4F2, HLA-DR, and IL-2-R. These observations suggest that sialophorin functions in T cell activation.
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PMID:Sialophorin, a surface sialoglycoprotein defective in the Wiskott-Aldrich syndrome, is involved in human T lymphocyte proliferation. 357 1

We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister's for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS.
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PMID:Two sisters with clinical diagnosis of Wiskott-Aldrich syndrome: is the condition in the family autosomal recessive? 912 30

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally described as a clinical triad of thrombocytopenia with small platelets, eczema, and immunodeficiency. Impaired CD43 glycoprotein expression on lymphocytes is a typical hallmark of this disorder. The CD43 gene is located on chromosome 16, and the WAS gene, WASP, was recently isolated from the chromosome X p11.22-p11.23. This gene, mutated in WAS patients, encodes a protein that is likely to play a role in controlling the expression of CD43. However, the molecular mechanism(s) causing WAS are not yet known. Herein, we describe a three-generation family in which clinical and laboratory WAS features were expressed in six of nine subjects available for study. At variance with classic X-linked WAS, this disorder was characterized by the presence of thrombocytopenia with a broad spectrum of platelet size, including giant platelets, and was inherited as an autosomal dominant trait. This last finding led us to hypothesize a mutation of the CD43 gene. However, Southern blot analysis failed to detect structural abnormalities of this gene, and genotype analysis ruled out the possibility that a CD43 allele might be shared by the affected individuals. These findings indicate that an alteration(s) of an autosomal gene distinct from the CD43 gene is responsible for the disease. Thus, results from this family, providing the first observation of an autosomally transmitted WAS variant, indicate that genetic mechanism(s) leading to WAS are more complex than previously recognized.
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PMID:Wiskott-Aldrich syndrome: report of an autosomal dominant variant. 863 21


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