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)

This work investigated the functional role of nuclear factor-kappaB (NF-kappaB) in respiratory burst activity and in expression of the human phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase genes CYBB, CYBA, NCF1, and NCF2. U937 cells with a stably transfected repressor of NF-kappaB (IkappaBalpha-S32A/S36A) demonstrated significantly lower superoxide release and lower CYBB and NCF1 gene expression compared with control U937 cells. We further tested Epstein-Barr virus (EBV)-transformed B cells from patients with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), an inherited disorder of NF-kappaB function. Superoxide release and CYBB gene expression by EDA-ID cells were significantly decreased compared with healthy cells and similar to cells from patients with X-linked chronic granulomatous disease (X91(0) CGD). NCF1 gene expression in EDA-ID S32I cells was decreased compared with healthy control cells and similar to that in autosomal recessive (A47(0)) CGD cells. Gel shift assays demonstrated loss of recombinant human p50 binding to a NF-kappaB site 5' to the CYBB gene in U937 cells treated with NF-kappaB inhibitors, repressor-transfected U937 cells, and EDA-ID patients' cells. Zymosan phagocytosis was not affected by transfection of U937 cells with the NF-kappaB repressor. These studies show that NF-kappaB is necessary for CYBB and NCF1 gene expression and activation of the phagocyte NADPH oxidase in this model system.
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PMID:Essential role of nuclear factor-kappaB for NADPH oxidase activity in normal and anhidrotic ectodermal dysplasia leukocytes. 1947 Apr 38

Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappaB (NF-kappaB) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKKgamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappaB pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKKgamma bound to ks-vFLIP at 3.2 A. In addition to identifying and subsequently probing the ks-vFLIP-IKKgamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).
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PMID:Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. 1853 60

Hypomorphic mutations in nuclear factor kappa B essential modulator (NEMO) cause X-linked ectodermal dysplasia with immunodeficiency (X-ED-ID). Clinical manifestations in boys with X-ED-ID apart from ectodermal dysplasia and immunodeficiency include osteopetrosis, lymphedema, and colitis. Further description of atypical findings in this disorder is needed. Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is in its infancy, and how or whether non-immune manifestations of defective NEMO function are impacted by HSCT is poorly described. We report an interesting case of a boy with NEMO mutation who had symptoms reminiscent of Omenn's syndrome and small intestinal villous atrophy with features reminiscent of tufting enteropathy. We describe his treatment course as well as reconstitution of immune function and correction of osteopetrosis post-HSCT, and review the cases of allogeneic HSCT reported to date in the literature.
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PMID:Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes. 1922 23

Activation of nuclear factor-kappaB (NF-kappaB), a key mediator of inducible transcription in immunity, requires binding of NF-kappaB essential modulator (NEMO) to ubiquitinated substrates. Here, we report that the UBAN (ubiquitin binding in ABIN and NEMO) motif of NEMO selectively binds linear (head-to-tail) ubiquitin chains. Crystal structures of the UBAN motif revealed a parallel coiled-coil dimer that formed a heterotetrameric complex with two linear diubiquitin molecules. The UBAN dimer contacted all four ubiquitin moieties, and the integrity of each binding site was required for efficient NF-kappaB activation. Binding occurred via a surface on the proximal ubiquitin moiety and the canonical Ile44 surface on the distal one, thereby providing specificity for linear chain recognition. Residues of NEMO involved in binding linear ubiquitin chains are required for NF-kappaB activation by TNF-alpha and other agonists, providing an explanation for the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency.
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PMID:Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. 1930 52

The history and the lessons learned from hypohidrotic ectodermal dysplasia (HED) may serve as an example for the unraveling of the cause and pathogenesis of other ectodermal dysplasia syndromes by demonstrating that phenotypically identical syndromes (HED) can be caused by mutations in different genes (EDA, EDAR, EDARADD), that mutations in the same gene (EDA) can lead to different phenotypes (HED and selective tooth agenesis) and that mutations in genes further downstream in the same signaling pathway (NEMO) may modify the phenotype quite profoundly (incontinentia pigmenti (IP) and HED with immunodeficiency). But it also demonstrates that diligent phenotype characterization and classification is extremely helpful in uncovering the underlying genotype. We also present a new mutation in the EDA gene which causes selective tooth agenesis and demonstrates the phenotype variation that can be encountered in the ectodermal dysplasia syndrome (HED) with the highest prevalence worldwide.
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PMID:From ectodermal dysplasia to selective tooth agenesis. 1950 6

Hypohidrotic/anhidrotic ectodermal dysplasia is a rare inherited disorder characterized by hypohidrosis/anhidrosis, hypotrichosis, dysodontia and heat intolerance. Most common mode of transmission is X-linked recessive, showing complete expression in males, and only partial manifestations in the female carrier heterozygotes. Features like atrophic rhinitis, nasal and aural myiasis, syndactyly, cleft lip and/or palate, mental retardation and immunodeficiency are uncommonly seen in this syndrome. We hereby report a case of hypohidrotic ectodermal dysplasia with unusual features of atrophic rhinitis and nasal myiasis.
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PMID:Hypohidrotic ectodermal dysplasia with atrophic rhinitis and nasal myiasis. 1961 58

Bloody stools, diarrhea and perianal abscesses were observed from the age of two months infant. The boy received a BCG vaccination at the age of four months. The patient was diagnosed as having Crohn's disease at the age of six months by intestinal endoscopy. Based on the diagnosis, he was treated with nutrition therapy, salazosulfapyridine, and prednisolone. Fever of unknown origin occurred two months after he had taken azathioprine at the age of two years and two months. Mycobacterium tuberculosis was detected from a gastric aspirate, and he was diagnosed as having disseminated BCG infection by means of the multiplex PCR method. Chest CT showed miliary pulmonary nodules in both lungs on admission. Physical examination revealed enlarged lymphnodes, which were palpable around the neck and groin, and hepatomegaly. Laboratory data were within normal ranges except a slightly increased peripheral white blood cell and serum CRP level. He was treated with rifampicin (15 mg/kg/day), isoniazid (15 mg/kg/day) for 12 months, and streptomycin (25 mg/kg/day) for two months. He became afebrile a week after starting the treatment, and the miliary pulmonary nodules in both lungs had disappeared by 5 months after starting the treatment. An abnormality of the NEMO gene, which is the gene responsible for ectodermal dysplasia and immunodeficiency, was identified at the age of three years. It is assumed that an abnormality of the NEMO gene caused a latent BCG infection over a period of one year and ten months, and immunosuppressive medicine (azathioprine) induced a disseminated BCG infection. This case report supports that anti-tuberculosis medicine should be given to prevent disseminated BCG infection if an infant who receive immunosuppressive therapy is found to have an immune deficiency characterized by a mycobacterium infection after BCG vaccination.
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PMID:[A case of disseminated BCG infection found during treatment of an infant with Crohn's disease]. 1976 66

NEMO is an integral part of the IkappaB kinase complex and serves as a molecular switch by which the NF-kappaB signaling pathway can be regulated. Oligomerization and polyubiquitin (poly-Ub) binding, mediated through the regulatory CC2-LZ domain, were shown to be key features governing NEMO function, but the relationship between these two activities remains unclear. In this study, we solved the structure of this domain in complex with a designed ankyrin repeat protein, which helps its crystallization. We generated several NEMO mutants in this domain, including those associated with human diseases incontinentia pigmenti and immunodeficiency with or without anhidrotic ectodermal dysplasia. Analytical ultracentrifugation and thermal denaturation experiments were used to evaluate the dimerization properties of these mutants. A fluorescence-based assay was developed, as well, to quantify the interaction to monoubiquitin and poly-Ub chains. Moreover, the effect of these mutations was investigated for the full-length protein. We show that a proper folding of the ubiquitin-binding domain, termed NOA/UBAN/NUB, into a stable coiled-coil dimer is required but not sufficient for efficient interaction with poly-Ub. In addition, we show that binding to poly-Ub and, to a lesser extent, to monoubiquitin increases the stability of the NOA coiled-coil dimer. Collectively, these data provide structural insights into how several pathological mutations within and outside of the CC2-LZ's NOA ubiquitin binding site affect IkappaB kinase activation in the NF-kappaB signaling pathway.
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PMID:DARPin-assisted crystallography of the CC2-LZ domain of NEMO reveals a coupling between dimerization and ubiquitin binding. 1985 4

Store-operated Ca2+ entry (SOCE) is an important Ca2+ influx pathway in many non-excitable and some excitable cells. It is regulated by the filling state of intracellular Ca2+ stores, notably the endoplasmic reticulum (ER). Reduction in [Ca2+]ER results in activation of plasma membrane Ca2+ channels that mediate sustained Ca2+ influx which is required for many cell functions as well as refilling of Ca2+ stores. The Ca2+ release activated Ca2+ (CRAC) channel is the best characterized SOC channel with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel, long mysterious, have been defined. ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER, and activates the CRAC channel upon store depletion by binding to ORAI1. Both proteins are widely expressed in many tissues in both human and mouse consistent with the widespread prevalence of SOCE and CRAC channel currents in many cells types. CRAC channelopathies in human patients with mutations in STIM1 and ORAI1 are characterized by abolished CRAC channel currents, lack of SOCE and-clinically-immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia. This article reviews the role of ORAI and STIM proteins for SOCE and CRAC channel function in a variety of cell types and tissues and compares the phenotypes of ORAI1 and STIM1-deficient human patients and mice with targeted deletion of Orai and Stim genes.
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PMID:CRAC channelopathies. 2011 71

Lymphocyte activation requires Ca(2+) influx through specialized Ca(2+) channels in the plasma membrane. In T cells the predominant Ca(2+) channel is the Ca(2+) release activated Ca(2+) (CRAC) channel encoded by the gene ORAI1. ORAI1 is activated by stromal interaction molecule (STIM) 1 that is localized in the ER where it senses the concentration of stored Ca(2+). Following antigen binding to immunoreceptors such as the TCR, ER Ca(2+) stores are depleted, STIM1 is activated and ORAI1-CRAC channels open resulting in what is referred to as store-operated Ca(2+) entry (SOCE). Mutations in ORAI1 and STIM1 genes in human patients that lead to expression of non-functional ORAI1 or complete lack of ORAI1 or STIM1 protein are associated with a unique clinical phenotype that is characterized by immunodeficiency, muscular hypotonia and anhydrotic ectodermal dysplasia, as well as, in the case of STIM1 deficiency, autoimmunity and lymphoproliferative disease. The immunodeficiency in these patients is due to a severe defect in T cell activation but not in lymphocyte development. This review describes the immunological and non-immunological phenotypes of patients with defects in SOCE and CRAC channel function and discusses them in the context of similar immunodeficiency diseases and animal models of ORAI1 and STIM1 function.
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PMID:Immunodeficiency due to mutations in ORAI1 and STIM1. 2018 84


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