Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperimmunoglobulin-E syndrome (HIES) is one of the primary immunodeficiency with the manifestations of recurrent infections especially with Staphylococcus aureus, characteristic facies, hyperextensibility of joints, multiple bone fractures, scoliosis, and delayed shedding of the primary teeth. It is a multisystem disease of autosomal dominant or recessive inheritance. Recently, the genetic causes of HIES (STAT3, TYK2, and DOCK8) were clarified.
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PMID:[Recent advances in the pathogenesis of hyper IgE syndrome]. 2019 May 5

Hyper-immunoglobulin E recurrent infection syndromes (HIES) have distinct features, with identified associated mutations of STAT3, TYK2, and DOCK8. Among 197 Taiwanese patients with primary immunodeficiency on a referral-base of over 23 million inhabitants, STAT3 (R382W and Q469R) and DOCK8 mutations (exon 1-9 deletion) were identified in two patients each from six AD-HIES and five AR-HIES patients, respectively. Aside from decreased Th17 and memory B cells, characteristic facies and pneumatocele were not mutually exclusive regardless of STAT3 and DOCK8 mutations. One with novel DOCK8 deletion had notable cytomegalovirus retinitis, cerebral vasculitis, lead deposition, and amenorrhea. In adolescence, three AD-HIES patients without STAT3 mutation died of myocardial infarction, staphylococcus sepsis, and proteus sepsis while receiving chemotherapy for lymphoma. Close follow-up of the HIES phenotype rather than identifying genetic mutations should be the cornerstone of intervention at this juncture because of relatively lower percentage of identifying mutations in Taiwanese HIES (4/11; 36.5%).
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PMID:Clinical, immunological and genetic features in Taiwanese patients with the phenotype of hyper-immunoglobulin E recurrent infection syndromes (HIES). 2132 46

Metastasis is considered a dynamic process in tumor development that is related to abnormal migration and invasion. Tumor cells can move as individual cells in two interconvertible modes: mesenchymal-type and amoeboid. Previously, we reported that the interaction between CD147 and Annexin II can inhibit the amoeboid movement in hepatocellular carcinoma (HCC) cells. However, the mechanism of CD147 involved in mesenchymal movement is still unclear. Notably, our results show overexpression of CD147 led to mesenchymal-type movement in HCC cells. Evidence indicated that the mesenchymal-type cell movement induced by CD147 was Src dependent, as observed by confocal microscopy and Rac1 activity assay. The phosphorylation of Src (pY416-Src) can be up-regulated by CD147, and this regulation is mediated by focal adhesion kinase (FAK). Next, we identified DOCK8 as a GEF for Rac1, a key molecule driving mesenchymal-type movement. We also found that Src promotes STAT3 phosphorylation and STAT3 facilitates DOCK8 transcription, thus enhancing DOCK8 expression and Rac1 activation. This study provides a novel mechanism of CD147 regulating mesenchymal-type movement in HCC cells.
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PMID:CD147 promotes Src-dependent activation of Rac1 signaling through STAT3/DOCK8 during the motility of hepatocellular carcinoma cells. 2542 19

In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules. However, in some patients with the relevant phenotype, mutations in these molecules are not identified, suggesting additional genetic etiologies of HIES not yet discovered. As the immunological and molecular basis of HIES is being unraveled, important insights are emerging that may have implications for our understanding of basic principles of immunology and protective immunity as well as for the pathogenesis and clinical management of patients with these complex and challenging PIDs. In this review, are presented the current knowledge on the clinical presentation, infectious phenotype, and the genetic and immunological pathogenesis of hyper-IgE syndromes as well as some other PIDs with elevated levels of IgE.
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PMID:Primary Immunodeficiencies with Elevated IgE. 2597 1

Combined immunodeficiencies (CIDs) include a group of inherited monogenic disorders. CIDs are characterized by defective cellular and humoral immunities that lead to severe infections. CIDs can be classified according to immunologic phenotypes as T(-)B(-)NK(-) CID, T(-)B(-)NK(+) CID, T(-)B(+)NK(-) CID and T(-)B(+)NK(+) CID. In a 20-year period, from 1994 to 2014, a total of 40 CID patients were diagnosed at the Pediatric Immunology of Erciyes University Medical Faculty in Kayseri, Turkey. The gender ratio (F/M) was 3/5. The median age at the onset of symptoms was 2 months (range, 15 days - 15 years). Of the 14 T(-)B(-)NK(-) CIDs, 6, 2 (siblings), 1, 1 and 4 had a mutation in the ADA, PNP, Artemis, RAG1 genes and unknown genetic diagnosis respectively. Of the 15 T(-)B(-)NK(+) CIDs, 3, 2 (siblings) and 10 had a mutation in the RAG1, XLF/Cernunnos genes and unknown genetic diagnosis respectively. Of the 9 T(-)B(+)NK(-) CIDs, 2 siblings, 1, 1 and 5 had a mutation in the ZAP70, IL2RG, DOCK8 genes and unknown genetic diagnosis respectively. Of the 2 T(-)B(+)NK(+) CIDs, 2 had a mutation in the MAGT1 and ZAP70 genes respectively. Of the 40 CIDs, 26 (65%) were died and 14 (35%) are alive. Eight patients received HSCT (hematopoietic stem cell transplantation) with 62.5% survival rate. As a result, patients presented with severe infections in the first months of life have to be examined for CIDs. Shortening time of diagnosis would increase chance of HSCT as life-saving treatment in the CID patients.
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PMID:Combined immunodeficiencies: twenty years experience from a single center in Turkey. 2709 30

A hyper-IgE syndrome is a rare immunodeficiesncy disease, often accompanied by high serum IgE. It often characterized by facial features, repeated skin infections, eczema and pulmonary infection, including autosomal dominant HIES (AD-HIES) and autosomal recessive HIES (AR-HIES). AR-HIES is caused by mutations in STAT3, which is presented as connective tissue, bone, vascular disease, and high brain white matter signal. AD-HIES is mainly caused by mutations in DOCK8 and TYK2, which is presented as severe viral infection and poor prognosis. The treatment for Hyper-IgE syndromes is mainly to control infection, skin care and other symptomatic treatment, if necessary, should be done as early as possible hematopoietic stem cell transplantation. This article reviews the clinical manifestations, pathogenesis and treatment of high IgE syndrome.
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PMID:[Hyper-IgE syndromes]. 2977 11

The advent of flow cytometry has revolutionized the way we approach our research and answer specific scientific questions. The flow cytometer has also become a mainstream diagnostic tool in most hospital and pathology laboratories around the world. In particular the application of flow cytometry has been instrumental to the diagnosis of primary immunodeficiencies (PIDs) that result from monogenic mutations in key genes of the hematopoietic, and occasionally non-hematopoietic, systems. The far-reaching applicability of flow cytometry is in part due to the remarkable sensitivity, down to the single-cell level, of flow-based assays and the extremely user-friendly platforms that enable comprehensive analysis, data interpretation, and importantly, robust and rapid methods for diagnosing PIDs. A prime example is the absence of peripheral blood B cells in patients with agammaglobulinemia due to mutations in BTK or related genes in the BCR signaling pathway. Similarly, the development of intracellular staining protocols to detect expression of SAP, XIAP, or DOCK8 expedites the rapid diagnosis of the X-linked lymphoproliferative diseases or an autosomal recessive form of hyper-IgE syndrome (HIES), respectively. It has also become evident that distinct cohorts of PID patients exhibit unique "lymphocyte phenotypic signatures" that are often diagnostic even prior to identifying the genetic lesion. Flow cytometry-based sorting provides a technique for separating specific subsets of immune cells such that they can be studied in isolation. Thus, flow-based assays can be utilized to measure immune cell function in patients with PIDs, such as degranulation by cytotoxic cells, cytokine expression by many immune cells (i.e., CD4⁺ and CD8⁺ T cells, macrophages etc.), B-cell differentiation, and phagocyte respiratory burst in vitro. These assays can also be performed using unfractionated PBMCs, provided the caveat that the composition of lymphocytes between healthy donors and the PID patients under investigation is recognized. These functional deficits can assist not only in the clinical diagnosis of PIDs, but also reveal mechanisms of disease pathogenesis. As we move into the next generation of multiparameter flow cytometers, here we review some of our experiences in the use of flow cytometry in the study, diagnosis, and unraveling the pathophysiology of PIDs.
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PMID:Flow Cytometric-Based Analysis of Defects in Lymphocyte Differentiation and Function Due to Inborn Errors of Immunity. 3155 44

Early detection of Primary Immunodeficiencies Disorders (PIDDs) is of paramount importance for effective treatment and disease management. Many PIDDs would be strong candidates for newborn screening (NBS) if robust screening methods could identify patients from dried blood spots (DBS) during the neonatal period. As majority of congenital PIDDs result in the reduction or absence of specific proteins, direct quantification of these target proteins represents an attractive potential screening tool. Unfortunately, detection is often limited by the extremely low protein concentrations in blood cells and limited blood volume present in DBS. We have recently developed a robust novel method for quantification of low abundance proteins in DBS for PIDDs using peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-SRM). Here, we further generated a multiplexed Immuno-SRM panel for simultaneous screening of eight signature peptides representing five PIDD-specific and two cell-type specific proteins from DBS. In samples from 28 PIDD patients including two carriers, representing X-Linked Agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-Linked Chronic Granulomatous Disease (XL-CGD), DOCK8 Deficiency and ADA deficiency, peptides representing each disease are significantly reduced relative to normal controls and patient identification had excellent agreement with clinical and molecular diagnosis. Also included in the multiplex panel are cell specific markers for platelets (CD42) and Natural Killer Cells (CD56). In patients with WAS, CD42 levels were found to be significantly reduced consistent with characteristic thrombocytopenia. A patient with WAS analyzed before and after bone marrow transplant showed normalized WAS protein and platelet CD42 after treatment highlighting the ability of immuno-SRM to monitor the effects of PIDD treatment. The assay was readily reproduced in two separate laboratories with similar analytical performance and complete agreement in patient diagnosis demonstrating the effective standardized methods. A high-throughput Immuno-SRM method screens PIDD-specific peptides in a 2.5-min runtime meeting high volume NBS workflow requirements was also demonstrated in this report. This high-throughput method returned identical results to the standard Immuno-SRM PIDD panel. Immuno-SRM peptide analysis represents a robust potential clinical diagnostic for identifying and studying PIDD patients from easily collected and shipped DBS and supports a significant potential for early PIDD diagnosis through newborn screening.
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PMID:Multiplexed Proteomic Analysis for Diagnosis and Screening of Five Primary Immunodeficiency Disorders From Dried Blood Spots. 3229 20

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5-10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.
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PMID:Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing. 3231 99

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