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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunodeficiency disorders can be classified on clinical grounds into two broad groups according to whether all features are the result of the immune defect (immunodeficiency syndromes) or whether many, even prominent, features cannot be explained by the immune defect (syndromes with immunodeficiency). X-linked agammaglobulinemia and X-linked chronic granulomatous disease are paradigmatic examples of immunodeficiency syndromes. Despite some overlap (for instance extra-immune symptoms, although minor, are present in several variants of severe combined immunodeficiency and chronic granulomatous disease) immunodeficiency syndromes and syndromes with immunodeficiency are easily distinguishable. Together with the pathogenetic classification of the WHO, the present approach to a clinical classification amplifies the operational concept of immunodeficiency also from a therapeutic point of view.
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PMID:Immunodeficiency and syndromes: a nosographic approach. 621 52

A panel of previously characterized monoclonal antibodies: OKT3, OKT4, OKT8, OKT10, OKT11, OKIa1, OKM2; 3A1, 4F2, UCTH1 and 5/9 were used to evaluate peripheral blood mononuclear cells in patients with severe primary immunodeficiencies: three patients with severe combined immunodeficiency, five with X-linked agammaglobulinemia, 20 with common variable hypogammaglobulinemia, 11 with IgA defect, and one with an unclassified form of T cell defect and hypogammaglobulinemia. Surface markers for T and B cells and in some cases functional assays, were also performed. Our results indicate a heterogeneous pattern in patients with severe combined immunodeficiency: one had peripheral blood mononuclear cells negative with all the monoclonal antibodies used; one had an increase in OKM2+ cells, whereas OKT3+ cells were absent; one had defect and imbalance of immunoregulatory T cell subpopulations. Major imbalances of T cell subsets were not detected in patients with X-linked agamma and IgA defect, whereas in some patients with common variable hypogammaglobulinemia an inversion of the physiological ratio between OKT4+ and OKT8+ cells was consistently detected. In an unclassified case of primary immunodeficiency, almost all peripheral blood mononuclear cells formed rosettes with sheep erythrocytes, but lacked antigens detected by monoclonal antibodies. Based on these observations, possible sites of defects in the T cell differentiation are discussed. We believe that monoclonal antibodies are useful for diagnosis, classification, and monitoring of therapy of primary immunodeficiencies.
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PMID:Monoclonal antibody analysis of T cell subsets in 40 patients with immunodeficiencies. 621 27

The failure to demonstrate normal humoral and cell-mediated immunity (CMI) in patients diagnosed as SCID is seen to reflect the varied pathogenesis of this syndrome. Two major groups of patients have been described, those with or without an associated absence of the enzyme ADA. The heterogeneity of the syndrome is expressed in variable inheritance patterns (particularly defined X-linked or autosomal recessive modes of inheritance), differing clinical presentations, and significant variability in laboratory findings. Some of this heterogeneity of laboratory findings may in fact be contributed to by the high incidence of infection or engraftment of maternal cells in utero. Common to all, however, is the profound deficiency of functional attributes of humoral and cell-mediated immunity. Insight into the biology of this immunodeficiency has advanced steadily in the last decade. Although initially hypothesized to represent a primary lymphoid stem-cell defect, newer technologies to identify and enumerate lymphocyte subpopulations and precursor lymphocytes have revealed the complexity of the disorder. This complexity may now be attributable to a number of abnormalities in the quantitative and qualitative differentiation of these lymphoid stem cells. Functional differentiation of lymphocytes is the result of a progressive and orderly sequence of events. In SCID, lymphocytes of both lineages may be arrested at specific and identifiable stages of maturation, leading to a deficiency of cell-mediated and humoral immunity. In many patients with SCID, the combined immune deficiency may be linked solely to a failure in the stepwise progression of T-cell differentiation.
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PMID:Diagnosis and classification of severe combined immunodeficiency disease. 636 Feb 47

The most debilitating human lymphoid deficiency disease, known as severe combined immunodeficiency (SCID), impairs the differentiation of both T and B lymphocytes. Affected infants are highly susceptible to recurring infections of viruses, fungi and bacteria and invariably die within 2 yr of birth. Inheritance of this congenital syndrome may show X-linked or autosomal recessive control. To date autosomal recessive inheritance of SCID has been observed in Arabian foals which represent the only known animal model of this disease syndrome but here we report an autosomal recessive mutation in mice that severely impairs lymphopoiesis. Mice homozygous for this mutation have few if any lymphocytes; consequently they are hypogammaglobulinaemic and deficient for immune functions mediated by T and B lymphocytes. These mice, therefore, represent a new model for investigating how lymphoid differentiation may be impaired in the disease state and regulated in the normal state.
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PMID:A severe combined immunodeficiency mutation in the mouse. 682 32

X-linked severe combined immunodeficiency syndrome (X-SCID) is a genetic disorder characterized by profound impairment of cell-mediated and humoral immunity. Affected children die of recurrent infections within 2 years of birth unless rescued by allogeneic transplantation from a suitable donor. Recently, the genetic defect responsible for X-linked SCID has been identified as a mutation in the gamma chain of the IL-2 receptor, a protein also shared by the IL-4 and IL-7 receptors and therefore now denoted the common gamma chain (gamma c). We report here the development of a high-titer amphotropic retroviral vector for transfer of gamma c. This vector was used to transfer a copy of the gamma c cDNA to murine 3T3 fibroblasts, CD34-enriched hematopoietic progenitor cells obtained from bone marrow and umbilical cord blood of normal donors, and to transplanted murine bone marrow progenitors. Murine 3T3 cells transduced by the retroviral vector were analyzed by Southern blot hybridization and Western transfer. Southern analysis confirmed the integration of unrearranged proviral DNA, and Western blot analysis demonstrated the expression of gamma c protein. CD34-enriched cells were infected with viral vectors bearing gamma c and grown in methylcellulose media. Individual colonies and pools of cells were analyzed 2 weeks later by polymerase chain reaction assay, which confirmed the proviral marking. The vector was also used to transfer a copy of the gamma c cDNA to murine bone marrow cells in a transplantation model. Infected marrow was transplanted into syngeneic Balb/c mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retroviral vector for gene therapy of X-linked severe combined immunodeficiency syndrome. 763 46

Human severe combined immunodeficiency (SCID), a syndrome of profoundly impaired cellular and humoral immunity, is most commonly caused by mutations in the X-linked gene for interleukin-2 (IL-2) receptor gamma chain (IL2RG). For mutational analysis of IL2RG in males with SCID, SSCP screening was followed by DNA sequencing. Of 40 IL2RG mutations found in unrelated SCID patients, 6 were point mutations at the CpG dinucleotide at cDNA 690-691, encoding amino acid R226. This residue lies in the extracellular domain of the protein in a region not previously recognized to be significantly conserved in the cytokine receptor gene family, 11 amino acids upstream from the highly conserved WSXWS motif. Three additional instances of mutation at another CpG dinucleotide at cDNA 879 produced a premature termination signal in the intracellular domain of IL2RG, resulting in loss of the SH2-homologous intracellular domain known to be essential for signaling from the IL-2 receptor complex. Mutations at these two hotspots constitute > 20% of the X-linked SCID mutations found by our group and a similar proportion of all reported IL2RG mutations.
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PMID:Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency. 766 84

Carrier detection in X-linked immunodeficiencies (X-SCID, WAS, XLA) relies on the demonstration of non-random X inactivation patterns in blood cell lineages. Only a limited number of cells are available after cell separation methods. PCR-based techniques are therefore necessary to analyze active and inactive X chromosomes. Amplifying a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme allows to distinguish between the paternal and maternal alleles and to identify their methylation status. DNA from B-, T-lymphocytes and total peripheral leukocytes of normal males, females and obligate carriers of X-linked immunodeficiencies were analyzed. The results of this PCR-based X inactivation assay are concordant with the standard methylation studies at the DXS255 locus using Southern blotting. This PCR assay provides a rapid and informative (heterozygosity > 90%) method in carrier detection of X-linked immunodeficiencies and other X-linked disorders, which show non-random X inactivation in cell lineages from the affected tissues.
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PMID:A PCR based X-chromosome inactivation assay for carrier detection in X-linked immunodeficiencies using differential methylation of the androgen receptor gene. 774 38

Chimpanzees are currently the only nonhuman animal model for reproducible propagation of hepatitis C virus (HCV). A chimeric mouse model was used for the induction of hepatitis C viremia, using BNX (beige/nude/X-linked immunodeficient) mice preconditioned by total body irradiation and reconstituted with SCID mouse bone marrow cells. HCV-infected liver fragments from patients with HCV RNA-positive sera were transplanted under the kidney capsule of the chimeric mice. HCV-specific RNA sequences were detected by reverse transcriptase nested polymerase chain reaction (RT-PCR) in serum of approximately 50% of grafted animals. In addition, normal liver specimens were incubated with HCV serum and transplanted into chimeric mice, leading to viremia in approximately 25% of animals. Sequential histologic evaluation of the liver implants, from day 2 to week 14 after transplantation, revealed loss of lobular architecture within the implants. However, viremia persisted for 10-50 days after transplantation. These results offer a new HCV model.
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PMID:Hepatitis C virus viremia in SCID-->BNX mouse chimera. 779 23

Neuronal changes in the brain of a Rett syndrome patient were examined in a frontal lobe biopsy performed at age 3 years and in the postmortem brain at age 15 years. In the brain biopsy, frontal cortex contained numerous scattered pyramidal neurons with cytoplasmic vacuolation and increased cytoplasmic density, with no neuronophagia or inflammation detected; electron microscopy showed these neurons to have large, lucent-appearing mitochondria, very abundant ribosomal content, and some lipofuscin granules. Postmortem brain 12 years later showed scattered neurons in frontal cortex, substantia nigra, and cerebellar folia, with increased electron density of the cytoplasm, stacks of ribosomal endoplasmic reticulum, and large amounts of disorganized membranous material, including autophagic-type organelles. Mitochondria of these neurons contained electron-dense, finely granular matrix inclusions; in the substantia nigra, some spherical mitochondrial inclusions completely filled the matrix space. Golgi preparations of (autopsy) frontal cortex and cerebellar folia showed truncation and thickening of dendrites and a degenerate appearance of cortical pyramidal neurons, similar to changes found in aged brain. Synaptophysin immunohistochemistry indicated that the density of synapses was not greatly altered compared to controls in frontal cortex and cerebellum. The patient also had a second genetic defect, severe combined immunodeficiency with thymic aplasia, which may be X-linked.
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PMID:Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. 782 37

Parallel genetic analysis of animal and human genetic diseases can facilitate the identification and characterization of the causative gene defects. For example, canine X-linked severe combined immunodeficiency (SCID) is characterized by clinical, pathological, and immunological manifestations similar to the most common form of human SCID. To derive a canine syntenic map including genes that in humans are located in proximal Xq, near human X-linked SCID, poly(TG) polymorphisms were identified at the canine phosphoglycerate kinase (PGK) and choroideremia (CHM) loci. These plus a polymorphic poly(CAG) sequence in exon 1 of the canine androgen receptor gene (AR) were used to genotype members of the colony informative for X-linked SCID. No recombinations among SCIDX1, AR, PGK, or CHM were observed. Fluorescence in situ hybridization localized PGK and CHM to proximal Xq in the dog, in the same chromosomal location occupied by the human genes. Somatic cell hybrid analysis and methylation differences at AR demonstrated that female dogs carrying X-linked SCID have the same lymphocyte-limited skewed X-chromosome inactivation patterns as human carriers. These genetic and phenotypic findings provide evidence that mutations in the same gene, now identified as the gamma chain of the IL-2 receptor, cause canine and human X-linked SCID. This approach is an efficient method for comparative gene mapping and disease identification.
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PMID:Comparative mapping of canine and human proximal Xq and genetic analysis of canine X-linked severe combined immunodeficiency. 782 3


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