Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunodeficient patients have an increased incidence of neoplasms, whether the immunodeficiency is due to genetic disorder, the acquired immunodeficiency syndrome (AIDS), or immunosuppressive therapy. Leiomyosarcoma (LMS) is a rare neoplasm, even if its incidence has increased because of AIDS. Less than fifteen cases were described after organ transplantation. An intracranial localization is exceptional (five cases in the literature) and was never described after organ transplantation, to our knowledge. Our present report focuses on a 45-year-old immunocompromised patient, who received immunosuppressive therapy for renal transplantation. He suffered from atypical peri-orbital headaches six months after transplantation and a mass involving the cavernous sinus was identified. Surgical biopsy was performed. Histologic examination revealed a LMS. Epstein-Barr virus was identified by quantitative polymerase chain reaction in the LMS. Immunosuppression was reduced, the patient received adriamycin and protontherapy was realized. He died two years after the transplantation because of tumor progression and kidney failure.
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PMID:[Primary leiomyosarcoma of the cavernous sinus associated with Epstein-Barr virus in a kidney graft]. 1471 28

The activation of the I-kappaB kinase (IKK) complex by TNF or LPS stimulates phosphorylation and degradation of I-kappaBalpha, leading to the nuclear translocation of NF-kappaB. The IKK complex is mainly composed of two catalytic subunits, IKKalpha and IKKbeta, and a chaperon subunit IKKgamma. Although IKKgamma does not have catalytic activity, it is essential for IKK activation induced by multiple stimuli. Importantly, the key residue cysteine 417 at the zinc finger domain of IKKgamma has been found to be mutated to arginine (IKKgammaC417R) in a human genetic disorder called the anhydrotic ectodermal dysplasia with immunodeficiency. To understand the underlying mechanisms of immunodeficiency, we examined whether the IKKgammaC417R mutant modified IKK activation and NF-kappaB transcription stimulated by LPS or TNF in human monocytes. We found that overexpression of IKKgammaC417R severely impaired LPS- and TNF-induced I-kappaBalpha phosphorylation and degradation in a dominant-negative fashion. Also, LPS- and TNF-induced NF-kappaB transcription was inhibited by IKKgammaC417R. The reconstitution of IKKgamma, but not IKKgammaC417R, in IKKgamma-deficient cells restored NF-kappaB signaling, indicating the zinc finger structure of IKKgamma plays a key role in IKK activation. Moreover, C417R mutation in IKKgamma abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKKbeta. Collectively, our results indicated that the zinc finger structure of IKKgamma plays a key role in LPS- and TNF-induced NF-kappaB activation. The anhydrotic ectodermal dysplasia with immunodeficiency patients' immunodeficiency may be associated with NF-kappaB defect in response to bacterial stimulation.
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PMID:The zinc finger mutation C417R of I-kappa B kinase gamma impairs lipopolysaccharide- and TNF-mediated NF-kappa B activation through inhibiting phosphorylation of the I-kappa B kinase beta activation loop. 1476 16

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by growth deficiency, unusual facies, sun-sensitive telangiectatic erythema, immunodeficiency and predisposition to cancer. The causative gene for Bloom syndrome is BLM, which encodes the BLM RecQ helicase homolog protein. The first part of this review describes a long-term follow-up study of two Bloom syndrome siblings. Subsequently, the focus is placed on the functional domains of BLM. Laboratory diagnosis of Bloom syndrome by detecting mutations in BLM is laborious and impractical, unless there are common mutations in a population. Immunoblot and immunohistochemical analyses for the detection of the BLM protein using a polyclonal BLM antibody, which are useful approaches for clinical diagnosis of Bloom syndrome, are also described. In addition, a useful adjunct for the diagnosis of Bloom syndrome in terms of the BLM function is investigated, since disease cells must have the defective BLM helicase function. This review also discusses the nuclear localization signal of BLM, the proteins that interact with BLM and tumors originating from Bloom syndrome.
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PMID:Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. 1513 5

The human genetic disorder, Nijmegen breakage syndrome, is characterized by radiosensitivity, immunodeficiency, chromosomal instability and an increased risk for cancer of the lymphatic system. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double strand breaks and in cell cycle checkpoints. Most patients are homozygous for a founder mutation, a 5 bp deletion, which might not be a null mutation, as functionally relevant truncated nibrin proteins are observed, at least in vitro. In agreement with this hypothesis, null mutation of the homologous gene, Nbn, is lethal in mice. Here, we have used Cre recombinase/loxP technology to generate an inducible Nbn null mutation allowing the examination of DNA-repair and cell cycle-checkpoints in the complete absence of nibrin. Induction of Nbn null mutation leads to the loss of the G2/M checkpoint, increased chromosome damage, radiomimetic-sensitivity and cell death. In vivo, this particularly affects the lymphatic tissues, bone marrow, thymus and spleen, whereas liver, kidney and muscle are hardly affected. In vitro, null mutant murine fibroblasts can be rescued from cell death by transfer of human nibrin cDNA and, more significantly, by a cDNA carrying the 5 bp deletion. This demonstrates, for the first time, that the common human mutation is hypomorphic and that the expression of a truncated protein is sufficient to restore nibrin's vital cellular functions.
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PMID:An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. 1533 89

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasias of the face, sun sensitivity, stunted growth, and immunodeficiency. Chromosome instability syndromes have a common feature, being associated at high frequency with neoplasia. BS is considered as one of the chromosome instability syndromes since the fibroblasts or lymphocytes of BS patients show excessive spontaneous chromosome instability. The causative gene of BS (BLM) was identified as a RecQ helicase homologue. In this review, we showed the characteristic phenotypes of BS, especially two Japanese siblings. In the latter of the review, the functional domains of BLM, those are nuclear localization signal and the interacting proteins such as ATM, are shown. Several lines of reports indicates that BLM helicase is involved in the re-initiation of DNA replication at sites where replication forks have arrested or collapsed. To elucidate the precise function of RecQ helicase in DNA repair and replication aims not only to improve our understanding of the molecular basis for tumorigenesis, but also to extend the range of potential therapeutic targets.
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PMID:The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining. 1547 92

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasias of the face, sun sensitivity, stunted growth, and immunodeficiency. Chromosome instability syndromes have a common feature, being associated at high frequency with neoplasia. BS is considered as one of the chromosome instability syndromes since the fibroblasts or lymphocytes of BS patients show excessive spontaneous chromosome instability. The causative gene of BS (BLM) was identified as a RecQ helicase homologue. In this review, we showed the characteristic phenotypes of BS, especially two Japanese siblings. In the latter of the review, the functional domains of BLM, those are nuclear localization signal and the interacting proteins such as ATM, are shown. Several lines of reports indicates that BLM helicase is involved in the re-initiation of DNA replication at sites where replication forks have arrested or collapsed. To elucidate the precise function of RecQ helicase in DNA repair and replication aims not only to improve our understanding of the molecular basis for tumorigenesis, but also to extend the range of potential therapeutic targets.
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PMID:The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining. 1549 27

Bloom's syndrome (BS) is a rare human genetic disorder characterized by dwarfism, immunodeficiency, genomic instability and cancer predisposition. We have previously purified three complexes containing BLM, the helicase mutated in this disease. Here we demonstrate that BLAP75, a novel protein containing a putative OB-fold nucleic acid binding domain, is an integral component of BLM complexes, and is essential for their stability in vivo. Consistent with a role in BLM-mediated processes, BLAP75 colocalizes with BLM in subnuclear foci in response to DNA damage, and its depletion impairs the recruitment of BLM to these foci. Depletion of BLAP75 by siRNA also results in deficient phosphorylation of BLM during mitosis, as well as defective cell proliferation. Moreover, cells depleted of BLAP75 display an increased level of sister-chromatid exchange, similar to cells depleted of BLM by siRNA. Thus, BLAP75 is an essential component of the BLM-associated cellular machinery that maintains genome integrity.
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PMID:BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity. 1577 63

The Wiskott-Aldrich syndrome is a rare genetic disorder due to mutations in the WAS gene situated on chromosome X. It is comprised of microthrombocytopenia, eczema and immunodeficiency. However, the phenotypical presentation may vary as to the number and intensity of its manifestations. A milder form of Wiskott-Aldrich syndrome is known as the X-linked thrombocytopenia. We independently found eight individual or familial cases with the V75M substitution (9.76%). This high incidence was partly accounted for by the fact that three cases turned out to be related. The V75M mutation is recurrent, however, due to a CpG island. A genuine homozygous female patient was found. She showed microthrombocytopenia and infections to the same degree as her hemizygous father and brother. The WAS protein was decreased in a comparable fashion in the hemizygotes and the homozygote as well. Its amount was about 10% and 15% of normal in platelets and mononucleated white cells, respectively. In all patients was the picture consistent with XLT.
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PMID:Recurrent V75M mutation within the Wiskott-Aldrich syndrome protein: description of a homozygous female patient. 1594 11

The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of approximately 70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.
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PMID:Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein. 1684 Apr 38

Leukocyte adhesion deficiency (LAD) is a rare primary immunodeficiency inherited as an autosomal recessive genetic disorder. LAD was suspected in a four days old girl. She was born from healthy first cousins. A family history of a boy who died from omphalitis and sepsis was reported. Our patient had the severe form, she had delayed umbilical cord separation and suffered recurrent infections. She had a deletion of the G at position 1497. The patient received bone marrow transplantation from her HLA-identical mother at age of 14 months. She is now 9 years old and in good health.
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PMID:[Deficient expression of leukocyte adhesion proteins. A new Tunisian case]. 1703 42


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