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 striking number of human and murine immunodeficiency disorders which map to the X chromosome suggests that genes localized on this chromosome must have important roles in lymphocyte development. At least seven distinct disorders in the human and two in the mouse disrupt lymphocyte maturation, particularly that of B cells, at characteristic stages. As functional genes mapping to the X chromosome in one mammal are found on the X chromosome in all other mammals, the same genes regulating lymphocyte development are expected to be found on the X chromosome in mouse and man. Investigations into the possible mechanisms of these X-linked disorders have been hampered by the lack of molecular probes for the genes or gene products affected; because of this, and the possibility of correlating one or more of the several hundred B- or T-cell-specific genes with a specific mutation, we surveyed 15 different B- and T-cell-specific cDNA clones for localization to the X chromosome. We report here the characterization of one of these murine cDNA clones, which hybridizes with a large, X-linked gene family, designated XLR (X-linked, lymphocyte-regulated). We show that the XLR gene family is closely linked to the X-linked immunodeficiency described in the CBA/N mouse strain (xid), by restriction fragment length polymorphism (RFLP) analysis of DNA from mice congeneic for xid. This finding, together with data on the expression of the XLR locus in B cells, indicates that this gene family either includes the locus defined by the xid mutation or is adjacent to it in a gene complex which may be important in lymphocyte differentiation.
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PMID:Isolation of a cDNA clone corresponding to an X-linked gene family (XLR) closely linked to the murine immunodeficiency disorder xid. 298 75

Previous studies demonstrate that Ly-1 B cells and their progenitors are clearly detectable in peritoneum in normal mice. In this publication, we show (a) that peritoneal Ly-1 B cells resemble splenic Ly-1 B cells with respect to surface marker expression and functional activity (autoantibody production); (b) that Ly-1 B frequencies in peritoneum are considerably higher than in spleen; and (c) that genetic mechanisms reduce peritoneal Ly-1 B frequencies to minimal levels in SJL-related mice and to below detectability in CBA/N and other mice with the X-linked immunodeficiency (Xid). In addition, we show that that peritoneal (and perhaps splenic) Ly-1 B populations demonstrate an unique bias in immunoglobulin commitment. That is, they are selectively enriched for cells that express IgM heavy chains in association with lambda light chains. Thus, as a whole, evidence presented here defines the peritoneum as a tightly regulated lymphocyte compartment that normally houses a large population of mature Ly-1 B cells with distinctive functional properties.
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PMID:Peritoneal Ly-1 B cells: genetic control, autoantibody production, increased lambda light chain expression. 308 83

CNA/N mice bearing the X-linked immunodeficiency (xid) gene(s) demonstrate overall decreased numbers of B-cells, impaired immune responses to TI-2 antigens and decreased serum IgM, IgG3 and to a lesser extent IgG1 and IgA. In these experiments we examined equal number of B-cells (cells capable of regeneration of surface Ig) from PP, MLN and spleens of xid and control mice for immunoglobulin gene expression. B-cells present in CBA/N mice exhibit control levels of Ig isotype-specific mRNA accumulation and transcription. Oligonucleotide probes directed against membrane and secreted exons of mu, gamma and alpha genes were synthesized and hybridized to B-cell RNA from CBA/N and CBA/J mice to determine relative levels of each isotype- and exon-specific mRNA. Results revealed decreased alpha s RNA: alpha m RNA in splenic B-cells of xid mice when compared to control animals. Northern blot analysis of total tissue polysomal RNA demonstrated enhanced expression of the (larger) membrane form of alpha-mRNA (alpha m-RNA) of CBA/N when compared to CBA/J mice. This was especially apparent in splenic preparations; these and other studies have shown that both control and xid PP and MLN express enhanced levels of the membrane forms of each Ig heavy chain isotype RNA when compared to splenic RNA levels. These data suggest the presence of a defective regulation of membrane and secreted alpha in B-cell subpopulations of xid mice.
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PMID:Immunoglobulin gene expression in xid mice: defective expression of secreted and membrane alpha-heavy chain RNA. 311 16

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disease characterized by immunodeficiency and severe thrombocytopenia in affected males, but no demonstrable clinical abnormalities in carrier females. Through analysis of the methylation patterns of X-linked genes that display restriction fragment length polymorphisms (RFLPs), we studied the pattern of X-chromosome inactivation in various cell populations from female relatives of patients with WAS. The peripheral blood T cells, granulocytes, and B cells of eight obligate WAS carriers were found to display specific patterns of X-chromosome inactivation clearly different from these of normal controls. Thus, carriers of WAS could be accurately identified using this analysis.
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PMID:Carrier detection in the Wiskott Aldrich syndrome. 326 54

Primary lymphoma of the central nervous system (CNS), including reticulum cell sarcoma, microglioma, and histiocytic lymphoma, represents less than 1% of all primary brain tumors. In the last 10 years, this tumor has tripled in frequency in the nonimmunosuppressed population. By 1991, the tumor will be the most common neurological neoplasm by virtue of the increase in sporadic occurrence and in the acquired immunodeficiency syndrome (AIDS) population. Three percent of AIDS patients will develop this tumor either prior to AIDS diagnosis or during their subsequent course. In addition to acquired immunosuppression, patients with inherited disorders (such as Wiskott-Aldrich syndrome, severe combined immunodeficiency, and X-linked immunodeficiency) and other acquired disorders of the immune system are predisposed to the development of CNS lymphoma. Immunological studies have suggested a role for Epstein-Barr virus in the production of this tumor. Although subtypes exist, non-Hodgkin's lymphoma of the CNS most commonly consists of histiocytic cells or large immunoblastic cells bearing B cell surface markers in close proximity to the lateral and third ventricles. Sixty percent of these deposits are multiple, and subarachnoid invasion is seen in one-quarter of patients. Vitreous involvement of the eye occurring prior to and during the course of CNS lymphoma has been noted in up to 25% of patients. The involvement of multiple areas of the neuraxis, the eye, and multiple intracranial sites often occurs in the absence of obvious systemic lymphoma. Therapeutic trials of brain radiation therapy are associated with median survivals of less than 1 year. Uniform complete responses of intracranial deposits are recorded following chemotherapy with high-dose intravenous methotrexate, CHOP (cyclophosphamide, hydroxydaunomycin/doxorubicin, Oncovin (vincristine), and prednisone), high-dose cytosine arabinoside, and intra-arterial methotrexate with barrier modification.
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PMID:Primary central nervous system lymphoma. 328 32

Three primary immunodeficiency conditions are discussed: X-linked agammaglobulinemia, severe combined immunodeficiency, and the X-linked lymphoproliferative syndrome. Each condition is associated with a fascinating history since publication of the original description. To a large extent, the immunologic features of these conditions have been defined. Now, the power of recombinant DNA technology is being employed to dissect the molecular mechanisms central to each disease. This review traces the history of these X-linked conditions. Particular emphasis is focused on the molecular defects thus far exposed. In the end, the knowledge provided by this technology will facilitate genetic counseling, define the nature of the gene defects, provide a logical rationale for therapy, and elucidate the role of the X chromosome in lymphocyte ontogeny.
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PMID:Molecular basis of selected primary immunodeficiency disorders. 331 86

This paper compares erythrocyte nucleotide levels in patients with eight different inherited purine or pyrimidine enzyme defects identified amongst a variety of patients referred predominantly for investigation of severe neurological abnormalities, or immunodeficiency syndromes. Characteristic nucleotide patterns were identified only in the six disorders (four involving purine and two pyrimidine metabolism) where there was clinical evidence of cellular toxicity. They were frequently related to the accumulation of abnormal metabolites in body fluids. These erythrocyte studies have demonstrated the following. 1. ATP depletion is not an invariable feature of adenosine deaminase (ADA) deficiency, but the accumulation of the deoxyribonucleotides dATP, or dGTP, is diagnostic of ADA, or purine nucleoside phosphorylase (PNP) deficiency, respectively. The early accumulation of dATP in foetal blood is a valuable aid to prenatal diagnosis of ADA deficiency. 2. GTP depletion appears to reflect the degree of CNS involvement in hypoxanthine-guanine phosphoribosyltransferase and PNP deficiency, as well as PP-ribose-P synthetase superactivity. Other diagnostic changes involving increased pyrimidine sugars and increased or decreased NAD levels, or ZTP in Lesch Nyhan erythrocytes, show no consistent correlation with the clinical manifestations. 3. These altered nucleotide levels afford a novel means for carrier detection of the X-linked defect associated with aberrant PP-ribose-P synthetase activity, where no other test is yet available. Measurement of erythrocyte nucleotide levels thus provides a simple and rapid aid to diagnosis and may sometimes be essential for determining prognosis, carrier detection, or monitoring therapy. These characteristic 'fingerprints' may give some insight into the mechanism by which the abnormal gene product produces disease. Such grossly altered nucleotide levels could also result in loss of erythrocyte flexibility, increased destruction and hence the anaemia, or other clinical manifestations, observed in some disorders.
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PMID:Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine or pyrimidine metabolism. 337 Aug 20

The Wiskott-Aldrich syndrome (WAS) is one of several human immunodeficiency diseases inherited as an X-linked trait. The location of WAS on the X chromosome is unknown. We have studied 10 kindreds segregating for WAS for linkage with cloned, polymorphic DNA markers and have demonstrated significant linkage between WAS and two loci, DXS14 and DXS7, that map to the proximal short arm of the X chromosome. Maximal logarithm of odds (lod scores) for WAS-DXS14 and WAS-DXS7 were 4.29 (at theta = 0.03) and 4.12 (at theta = 0.00), respectively. Linkage data between WAS and six marker loci indicate the order of the loci to be (DXYS1-DXS1)-WAS-DXS14-DXS7-(DXS84-OTC). These results suggest that the WAS locus lies within the pericentric region of the X chromosome and provide an initial step toward identifying the WAS gene and improving the genetic counseling of WAS families.
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PMID:Linkage of the Wiskott-Aldrich syndrome with polymorphic DNA sequences from the human X chromosome. 347 14

Mice were given single injections of sheep erythrocytes (SE) or polyvinylpyrrolidone (PVP) at various times after sublethal, whole-body irradiation (550 rad 60CO) and direct, antigen-specific, plaque-forming cell (PFC) responses were quantified. Irradiated mice did not respond to SE or PVP when immunized 15 d postirradiation (PI); by day 30 PI, the responses by irradiated mice were 40-126% of normal to SE and 3-38% of normal to PVP. The impaired recovery after irradiation of immune responses to PVP was not due to altered antigen dose requirements or altered time of peak PFC response and occurred after irradiation of mice by doses as low as 200 rad. Both athymic and euthymic mice had impaired responses to PVP after whole-body irradiation. The impaired response of irradiated mice to PVP was repaired by adoptive transfer of normal bone marrow, fetal liver, or spleen cells and also by spleen cell preparations enriched in Ig+ cells but not by spleen cell preparations enriched in Thy.1+ or Ig- cells. With the aid of additional antigens it was observed that by day 30 PI, mice had recovered ability to respond to the T-cell-dependent antigen SE and the T-cell-independent type-1 antigens 2,4,6-trinitrophenyl-Brucella abortus and butanol-extracted bacterial lipopolysaccharide, but at that time they gave impaired responses to the T-cell-independent type-2 antigens PVP, type III pneumococcal polysaccharide, and phenol-extracted bacterial lipopolysaccharide; they had an immune response pattern similar to that of CBA/N mice having an X-linked immunodeficiency.
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PMID:Differential recovery of antibody production potential after sublethal, whole-body irradiation of mice. 352 64

The pathogenesis of diabetes in C57BL/KsJ-db/db mice has been proposed to entail autoimmune mechanisms. We have combined immunodeficiency genes with the db mutation to determine whether beta cell necrosis and establishment of severe diabetes would occur in the absence of normal T and/or B lymphocyte functions. Inbred mice carrying the recessive mutations, severe combined immunodeficiency (scid), X-linked immunodeficiency (xid), nude (nu), and the Y-linked autoimmune accelerator (Yaa), were crossed with strains congenic for the db mutation. The diabetes syndrome was studied in double homozygotes produced in the F2 generation. In another experiment, C57BL/KsJ-db/db males were made T cell function deficient by adolescent thymectomy followed by lethal irradiation and bone marrow reconstitution. None of these manipulations served to prevent the induction of a severe diabetes syndrome in any of the model systems analyzed. Thus, diabetogenesis characterized by massive necrosis of the pancreatic beta cells and atrophy of the pancreatic islets was observed in both the absence of normal T cell function (as assessed by absence of T cell mitogen response) and humoral autoimmunity against beta cell antigens (insulin, retroviral p73). In conclusion, our data indicate that anti-beta cell autoimmunity is not a primary event in the etiopathogenesis of diabetes in the db/db mouse.
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PMID:Effect of immunodeficiency on diabetogenesis in genetically diabetic (db/db) mice. 355 24


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