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)

A fetus diagnosed with X-linked chronic granulomatous disease was transplanted with Thy-1(+)CD34(+) cells of paternal origin. The transplant was performed at 14 weeks gestation by ultrasound guided injection into the peritoneal cavity. The fetus was delivered at 38 weeks gestation after an otherwise uneventful pregnancy. Umbilical cord blood was collected and used to determine the level of peripheral blood chimerism as well as levels of functional engrafted cells. Flow cytometry was used to detect donor leukocytes identified as HLA-A2(-)B7(+) cells, whereas recipient cells were identified as HLA-A2(+)B7(-) cells. No evidence of donor cell engraftment above a level of 0.01% was found. PCR was used to detect HLA-DRB1*15(+) donor cells among the recipient's HLA-DRB1*15(-) cells, but no engraftment was seen with a sensitivity of 1:1000. The presence of functional, donor-derived neutrophils was assessed by flow cytometry using two different fluorescent dyes that measure reactive oxygen species generated by the phagocyte NADPH oxidase. No evidence of paternal-derived functional neutrophils above a level of 0.15% was observed. Peripheral blood and bone marrow samples were collected at 6 months of age. Neither sample showed engraftment by HLA typing using both flow cytometry and PCR. Functional phagocytes were also not observed. Furthermore, no indication of immunological tolerance specific for the donor cells was indicated by a mixed lymphocyte reaction assay performed at 6 months of age. While there appears to be no engraftment of the donor stem cells, the transplant caused no harm to the fetus and the child was healthy at 6 months of age. Analyses of fetal tissues, obtained from elective abortions, revealed that CD3(+) T cells and CD56(+)CD3(-) NK cells are present in the liver at 8 weeks gestation and in the blood by 9 weeks gestation. The presence of these lymphocytes may contribute to the lack of donor cell engraftment in the human fetus.
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PMID:Transplantation of a fetus with paternal Thy-1(+)CD34(+)cells for chronic granulomatous disease. 1131 64

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.
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PMID:Advances in the understanding and treatment of human severe combined immunodeficiency. 1133 59

Chronic granulomatous disease is caused by a genetic defect in the oxidase of phagocytic cells which results in increased susceptibility to recurrent infections. Conventional treatment includes the use of antimicrobials and interpheron-gamma. This study was performed to assess the clinical efficacy of allogeneic bone marrow transplantation in definitively correcting the functional underlying defect of chronic granulomatous disease. An 8-year-old boy with a rare type X-linked cytochrome b positive chronic granulomatous disease underwent allogeneic bone marrow transplantation after conditioning with busulfan and cyclophosphamide. The patient's HLA identical sister was marrow donor. The post-transplant outcome was uneventful. During the 9 year follow-up period the patient has been constantly free of infections, maintained an excellent clinical performance with full correction of the granulocyte functional defect. This case confirms that allogeneic bone marrow transplantation is the only treatment capable to cure chronic granulomatous disease to those patients who cannot be optimally treated with conventional therapy.
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PMID:Malignancy: X-Linked Cytochrome B Positive Chronic Granulomatous Disease treated by Bone Marrow Transplantation. 1139 72

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

Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immune-mediated diabetes is also heterogeneous with "monogenic", oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ(*) and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk.
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PMID:Genetic control of autoimmunity in Type I diabetes and associated disorders. 1210 41

As a single-gene defect in phagocytes, the X-linked form of chronic granulomatous disease (X-CGD) is a disorder potentially amenable to gene therapy by transfer of a functional copy of the gp91(phox) gene into hematopoietic stem cells (HSC). Although antimicrobial agents and interferon-gamma (IFN-gamma) have significantly improved its prognosis, CGD is still associated with high morbidity and mortality. The disease can be cured by bone marrow transplantation (BMT); however, BMT in CGD has been associated with unacceptably high rates of morbidity, mortality, and graft failure, except in very selected cases in which an HLA-identical donor is available. Prerequisites for a clinical gene therapy of CGD are an efficient mobilization of peripheral blood stem cells (PBSC) as well as the preservation of their viability and hematopoietic potential following transduction and ex vivo culture. We show that (i) mobilization and collection of CD34(+) cells after a 4-week IFN-gamma-free period by G-CSF results in sufficient numbers of cells for transplantation; (ii) the quality of collected stem cells is not altered in comparison to cells obtained from healthy volunteers as assessed by long-term culture initiating cells (LTC-IC) and progenitor cell expansion; (iii) retroviral transfer of the gp91(phox) gene under defined, serum-free conditions leads to high and stable reconstitution of the respiratory burst activity in X-CGD neutrophils derived from transduced CD34(+) progenitor and LTC-IC. Withdrawal of IFN-gamma in CGD patients may improve mobilization of CD34(+) stem cells by G-CSF. The gene transfer conditions established here are applicable to a clinical approach for gene therapy of X-CGD.
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PMID:Mobilization and transduction of CD34(+) peripheral blood stem cells in patients with X-linked chronic granulomatous disease. 1220 57

Immune-mediated tissue destruction or disregulation is the cause of multiple common, as well as rare, endocrine disorders including type 1 diabetes, Graves' disease, Hashimoto thyroiditis, and Addison's disease. Each of these disorders can be divided into a series of stages beginning with genetic susceptibility, environmental triggering events, and active autoimmunity, followed by metabolic abnormalities with overt disease. Common genetic susceptibility is suggested by the clustering of a series of disorders in the same individual and his or her family. A major portion of the genetic susceptibility lies in the HLA region, but for several disorders, mutation of transcription factors underlies disease susceptibility (eg, X-linked polyendocrinopathy, immune deficiency and diarrhea, and autoimmune polyendocrine syndrome type 1). With improving immunogenetic and pathogenic understanding, type 1A diabetes is now predictable, and excellent autoantibody screening assays are available. This knowledge, combined with studies in animal models, has led to trials for the prevention of diabetes. In addition, aberrant immunologic reactions (eg, insulin autoantibodies after insulin therapy, Graves' disease after monoclonal anti-T-cell therapy in multiple sclerosis) can complicate standard and experimental therapies. We therefore believe that an understanding of the immunogenetics and immunopathogenesis of endocrine disorders can aid in the prevention of morbidity and mortality for these related diseases.
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PMID:17. Immunologic endocrine disorders. 1259 8

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by an abnormal function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the phagocytic cells, which results in an increased susceptibility to severe bacterial and fungal infections. We report on a 12-year-old boy with X-linked CGD who was successfully treated with allogeneic bone marrow transplantation from an HLA-identical sibling following a conditioning regimen consisting of busulphan (BU, 16 mg/kg) and cyclophosphamide (CY, 200 mg/kg). At >2 years from transplant, the boy is in excellent clinical and hematological condition with full chimerism. Our patient is the 24th case of CGD transplanted from an HLA-identical sibling. A review of the literature revealed that 20 of 24 CGD patients are alive and disease free 1-7 years after transplant. Most of these patients were conditioned with the BUCY combination, which should be considered the recommended regimen.
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PMID:Allogeneic stem cell transplant from HLA-identical sibling for chronic granulomatous disease and review of the literature. 1263 56

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell (HSC) disorder in which an acquired somatic mutation of the X-linked PIGA gene results in a deficiency in GPI-anchored surface proteins. Clinically, PNH is dominated by a chronic hemolytic anemia, often associated with recurrent nocturnal exacerbations, neutropenia, thrombocytopenia, and thrombotic tendency. Allogenic bone marrow transplantation is the only potentially curative treatment for severe forms of PNH but is associated with a high treatment-related morbidity and mortality. HSC gene therapy could provide a new therapeutic option, especially when an HLA-matched donor is not available. To develop an efficient gene transfer approach, we have designed a new SIN lentiviral vector (TEPW) that contains the PIGA cDNA driven by the human elongation factor 1 alpha promoter, the central DNA flap of HIV-1, and the WPRE cassette. TEPW transduction led to a complete surface expression of the GPI anchor and CD59 in PIGA-deficient cell lines without any selection procedure. Moreover, efficient gene transfer was achieved in bone marrow and mobilized peripheral blood CD34(+) cells derived from two patients with severe PNH disease. This expression was stable during erythroid, myeloid, and megakaryocytic liquid culture differentiation. CD59 surface cell expression was fully restored during 5 weeks of long-term culture.
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PMID:A SIN lentiviral vector containing PIGA cDNA allows long-term phenotypic correction of CD34+-derived cells from patients with paroxysmal nocturnal hemoglobinuria. 1266 26

The wide association between urinary tract malformations and dysplastic kidneys, known as CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), could be caused by a single disorder of the embryonic development of the kidney and urinary tract. These complex patterns of development are under genetic control. A positive family history strongly suggests a genetic origin of these conditions. Linkage studies show an extreme genetic heterogenicity and an important phenotypic and clinical variability of the same mutation. Some urinary tract malformations have been investigated in the context of clinical syndromes. The renal-coloboma syndrome is an autosomal dominant human disease, secondary to mutation of the PAX2 transcription factor, characterized by optic nerve coloboma, renal anomalies and vesicoureteral reflux. However, most of the urinary tract anomalies can occur in isolation. Studies have shown the association of hereditary hydronephrosis with HLA antigens on chromosome 6 and the association of VUR with the mutations in a locus of chromosome 1. The higher frequency and severity of some uropathies in the male gender may be explained by a linkage-disequilibrium phenomenon or a X-linked transmission pattern. For example, the mutations in the AGTR2 gene on chromosome X were observed in animal models but not yet confirmed in human subjects. Finally, the ACE gene polymorphism is associated with a higher incidence of congenital hypo-dysplastic kidneys and represents a significant risk factor for the development of progressive renal damage.
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PMID:[Genetic basis for malformation-associated uropathy and renal dysplasia]. 1274 96


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