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

SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma-chain (gamma(c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.
 ...
PMID:A deletion in the gene encoding the CD45 antigen in a patient with SCID. 1114 14

The Internet contains scientific information in increasing amounts. It is possible to obtain the latest information, and Web services can easily be maintained and updated. We have set up three Internet services on immunodeficiencies. Immunodeficiency-related mutation infor mation is available in immunodeficiency mutation databases (IDbases). Currently 14 registries are distributed, including information about Bloom syndrome (BLMbase), X-linked agammaglobulinemia (BTKbase), X-linked and autosomal recessive chronic granulomatous diseases (CYBBbase for X-linked CGD, CYBAbase for p22(phox) deficiency, NCF1base for p47(phox) deficiency, NCF2base for p67(phox) deficiency), CD3gamma and CD3epsilon deficiencies (CD3Gbase, CD3Ebase), X-linked hyper-IgM syndrome (CD40Lbase), T-B+ severe combined immunodeficiency (JAK3base), V(D)J recombination defects (RAG1base, RAG2base), X-linked lymphoproliferative syndrome (SH2D1Abase), and ZAP-70 deficiency (ZAP70base). Information on laboratories analysing the genetic defects is collected to IDdiagnostics registry. Due to the rareness of immunodeficiencies there are very few laboratories performing genetic diagnostics. Such laboratories are listed in IDdiagnostics and physicians can use the registry to find a suitable laboratory for their diagnostic needs. Immunodeficiency Resource (IDR) is a comprehensive integrated knowledge base for all the information on immunode ficiencies, including clinical, biochemical, genetic, structural and computational data and analyses. All three services are available at http: //www.uta.fi/imt/bioinfo/.
 ...
PMID:Novel immunodeficiency data servers. 1121 2

Nonhuman primate model systems of autologous CD34+ cell transplant are the most effective means to assess the safety and capabilities of lentivirus vectors. Toward this end, we tested the efficiency of marking, gene expression, and transplant of bone marrow and peripheral blood CD34+ cells using a self-inactivating lentivirus vector (CS-Rh-MLV-E) bearing an internal murine leukemia virus long terminal repeat derived from a murine retrovirus adapted to replicate in rhesus macaques. In vitro cytokine stimulation was not required to achieve efficient transduction of CD34+ cells resulting in marking and gene expression of the reporter gene encoding enhanced green fluorescent protein (EGFP) following transplant of the CD34+ cells. Monkeys transplanted with mobilized peripheral blood CD34+ cells resulted in EGFP expression in 1 to 10% of multilineage peripheral blood cells, including red blood cells and platelets, stable for 15 months to date. The relative level of gene expression utilizing this vector is 2- to 10-fold greater than that utilizing a non-self-inactivating lentivirus vector bearing the cytomegalovirus immediate-early promoter. In contrast, in animals transplanted with autologous bone marrow CD34+ cells, multilineage EGFP expression was evident initially but diminished over time. We further tested our lentivirus vector system by demonstrating gene transfer of the human common gamma-chain cytokine receptor gene (gamma(c)), deficient in X-linked SCID patients and recently successfully used to treat disease. Marking was 0.42 and.001 HIV-1 vector DNA copy per 100 cells in two animals. To date, all EGFP- and gamma(c)-transplanted animals are healthy. This system may prove useful for expression of therapeutic genes in human hematopoietic cells.
 ...
PMID:Lentivirus vector-mediated hematopoietic stem cell gene transfer of common gamma-chain cytokine receptor in rhesus macaques. 1126 44

Human severe combined immunodeficiency (SCID) can result from mutations in any one of at least seven different genes, including those for adenosine deaminase, the common cytokine receptor gamma chain, Janus kinase 3, IL-7 receptor alpha chain, recombinase activation genes 1 and 2, and CD45. Except for adenosine deaminase, knowledge concerning the latter causes of human SCID has accrued since 1993. Advances in the treatment of this syndrome have been no less significant. Since 1982 it has been possible, by rigorous depletion of T cells from the donor marrow, to use related marrow donors other than HLA-identical siblings for successful treatment of infants with this condition. The success rate with the latter type of transplant exceeds 95% if a transplant can be performed within the first 3.5 mo of life, making early diagnosis crucial. Recently, gene therapy has also been successful in infants with X-linked SCID.
 ...
PMID:Advances in the understanding and treatment of human severe combined immunodeficiency. 1133 59

Childhood T-cell acute lymphoblastic leukemia (T-ALL) is one of the most common childhood cancers. It is reported that preconditioning sublethally irradiated immunodeficient NOD/SCID (nonobese diabetic/X-linked severe combined immunodeficient) mice with human cord blood mononuclear cells facilitates the engraftment, expansion, and dissemination in these mice of primary T-ALL cells obtained from patients at the time of diagnosis. Cells recovered from mouse bone marrow or spleen resembled the original leukemia cells from patients with respect to surface lineage markers and T-cell receptor Vbeta gene rearrangements. Moreover, the pattern of leukemia dissemination in mouse tissues, resulting in universally fatal leukemia, is reminiscent of the human clinical disease. In addition, the fidelity of the model to the human disease is documented with regard to the presence of morphologically identifiable human leukemia cells in mouse bone marrow and blood and the maintenance of leukemia-initiating capacity within the leukemia-engrafted mouse. Therefore, several lines of independent approaches are used to suggest that the engrafted cells are of human leukemia origin and are not derived from cord blood. The in vivo model described here should enable the study of the growth properties of primary T-ALL cells obtained from patients and should prove useful in evaluating the potential efficacy of therapeutic strategies directed toward T-ALL.
 ...
PMID:Preconditioning with fetal cord blood facilitates engraftment of primary childhood T-cell acute lymphoblastic leukemia in immunodeficient mice. 1134 52

Severe combined immunodeficiency (SCID) is a rare syndrome of profoundly impaired immunity, most often X-linked (XSCID). In past generations male infants with XSCID succumbed to infections during the first year of life, but prompt diagnosis and bone marrow transplantation currently make survival possible for over 80%. This treatment typically requires hospitalization for several months; thus, the burden on the family is considerable. We assessed the psychological impact on sibs of boys with XSCID. Forty adult sibs from families studied by J.M.P. were interviewed by J.H.F., and rating scales developed. The majority expressed distress over prolonged maternal absence during the affected child's hospitalization; 67% believed the mother had unsuccessfully mourned son(s) who died of XSCID. Half of the sibs reported that communication in the family about XSCID had been poor. Families with a spontaneous mutation were significantly more likely to report separation issues (P = 0.05), perhaps due to stronger maternal guilt. Family communication was significantly related to parental mourning (P = 0.001) and to survivor guilt (P = 0.05). Difficulties for daughters included desire to repair the mother's loss of her own child, as well as attempts to undo feelings of being flawed, by heightened wishes to bear a healthy son. In light of these findings we suggest: 1) bone marrow transplantation and the period of isolation places great stress on the family; parents need help balancing needs of well sibs with needs of the affected son; 2) parents need help with mourning the loss of a son so family secrets will not prevail; and 3) sibs, both bone marrow donors and non-donors, face psychological risks and need support.
 ...
PMID:Family pictures: growing up with a brother with X-linked severe combined immunodeficiency. 1142 56

Periodically the World Health Organization and currently the International Union of Immunology Societies publish a classification of primary immunodeficiency diseases (PID) that includes diagnostic and therapeutic guidelines. The latest of these publications dates from 1999 and includes a new group of PID, the proliferative autoimmune syndromes. Furthermore, new forms of severe combined immunodeficiency (SCID) and of recessive autosomal agammaglobulinemia are described. From the publication of this classification until the end of the year 2000 a minimum of three new PIDs have been described and a further two should probably be added. Progress in the molecular biology of these diseases has given rise not only to more accurate diagnosis but also to greater insight into the clinical spectrum of these diseases. A mutation or deletion in a gene can provoke the complete absence of its product; sometimes expression is partial or normal but functional activity is absent or defective. In certain cases, partial or defective activity causes variant forms of the disease presenting symptomatology or atypical cellular phenotype. In other cases, this is not cause of the variant form, which can appear in interfamilial cases sharing the same mutation. In these cases, these differences can be attributed to environmental factors or to other genes able to modify the affected gene. In this article we provide examples of variant forms in several PIDs. Some are late onset forms, such as X-linked agammaglobulinemias diagnosed in adults, since until diagnosis, clinical symptomatology was minimal. In adenosine-deaminase deficiency, a serious and highly lymphoproliferative form of SCID, patients have been described whose symptomatology began after the age of 20 years. Another SCID, RAG1 and RAG2 recombinase deficiency, may produce a typical form with a characteristic T-B-NK + phenotype, Omenn's syndrome, or forms with an unexpected T-B + NK + phenotype. Deficiency in common gamma chain receptor for IL-2 may produce phenotypical variants that can lead to diagnostic error. X-linked lymphoproliferative syndrome may present as fulminant infectious mononucleosis, as leukemia or lymphoma or as hipo- or agammaglobulinemia. Possibly, some patients diagnosed with common variable immunodeficiency or with x-linked agammaglobulinemia do in fact have this syndrome. Chronic granulomatous disease is usually of early-onset, but late-onset forms have been described. In one case the first clinical manifestation was produced when the patient was 60 years old. The above examples serve to highlight that, even though PIDs are usually suspected by pediatricians, in some cases the diagnosis may be missed by internists or non-pediatricians. Moreover, the clinical and laboratory findings of these variant forms must be determined to carry out an early diagnosis, which is essential for a favorable therapeutic outcome.
 ...
PMID:[Primary immunodeficiencies. Clinical features and variant forms]. 1143 82

Recent advances in gene transfer in human hematopoietic cells, combined with a better understanding of the genetic aspects of several immunodeficiencies, has offered new opportunities in the domain of gene therapy. Severe combined immunodeficiency (SCID) appear to represent a good model for the application of gene therapy, combining an expected selective advantage for transduced cells, an absence of immunological response to the vector and/or the therapeutic transgene, together with accessibility to hematopoietic stem cells (HSC). Ex vivo retroviral transduction of a therapeutic transgene in HSC prior to transplantation appears to be a particularly effective and long-lasting means of restoring the expression of a mutated gene in the lymphoid lineage. Furthermore, encouraging therapeutic benefits as a result of a gene therapy protocol for the treatment of X-linked severe combined immunodeficiencies (SCID-X1) invites many questions as to the reasons for this therapeutic benefit. This review outlines the results that have been achieved in gene therapy for SCID-X1, ADA-SCID as well as other types of SCID, and discusses the possible relationship between the physiopathology of each disease and the success of relevant trials.
 ...
PMID:Gene therapy of severe combined immunodeficiencies. 1143 25

Since the early 1990s, primary immunodeficiency (ID) disorders have played a major role in the development of human gene therapy. Adenosine deaminase (ADA) deficiency was the first disease to be treated with a gene therapy approach in humans, and was also the first condition for which therapeutic gene transfer into the hematopoietic stem cell has been attempted in the clinical arena. A series of encouraging results obtained in chronic granulomatous disease (CGD) patients have followed these pioneer experiments and preceded the very recent and exciting reports of successful genetic correction procedures performed in patients affected with the X-linked form of severe combined immunodeficiency (XSCID). The technical progress made in the field of gene transfer in recent years is mostly responsible for these clinical advances, and will be critical for future development of gene therapy approaches for other forms of IDs.
 ...
PMID:Gene therapy for immunodeficiency. 1189 66

A mutation (c.878T>A) in the common gamma chain (gamma(c)) causes an X-linked combined immunodeficiency (XCID) in a large kindred of British origin. In the disease, gamma(c) is expressed, but its binding to Jak3 is reduced. The immune deficiencies and clinical course were less marked in toddlers and school age children with XCID(L293Q) than in severe combined immunodeficiency (SCID). However, affected newborns were profoundly deficient in thymic size and T cells. In some affected infants, thymic size and numbers of T cells gradually increased during the first year. Their clinical course was relatively benign. In affected infants of one lineage, the number of blood T cells failed to increase substantially. They succumbed to opportunistic infections. T cell deficiencies in XCID(L293Q) progressively worsened during adolescence. Decreased thymic function, failure to rescue T cells from apoptosis, and replication senescence were possible causes. Blood T cells with the phenotype CD45RA(+)CD62L(+) (unstimulated T cells) were most depressed. CD4(+) T cells were also deficient in a specific marker of recent thymic emigrants, episomal DNA deletion circles created during TcR gene rearrangements. Apoptosis of T cells was increased, but neither apoptosis nor cell death was age-related. In contrast, telomere shortening in T cells increased with age. Unlike murine gamma(c) gene deletions, gamma delta T cells were prominent in affected adolescents and young adults. Furthermore, T cells with a V delta 2/V gamma 9 specificity declined with age and were replaced in the oldest male with a V delta 1 specificity. Thus, the mutation provides many insights concerning the role of gamma(c) in the biology of T cells.
 ...
PMID:Immune consequences of mutations in the human common gamma-chain gene. 1212 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>