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)

X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The neurologic symptoms suggested the diagnosis of Mohr-Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of the deletion.
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PMID:Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. 1785 39

To report the results of the first known cochlear implantation in a patient with deafness-dystonia-optic neuronopathy (DDON) syndrome (Mohr-Tranebaerg syndrome, DFN-1). DDON syndrome is an X-linked condition characterized by postlingual sensorineural hearing loss in early childhood followed by dystonia, psychosis, and optic atrophy in adolescence and adulthood. The gene responsible for the condition maps to Xq22 adjacent to the gene causally related to X-linked agammaglobulinemia. The audiometric characteristics of DDON syndrome are typical of auditory neuropathy, with spiral ganglion cells being the suspected site of pathology. Performance following cochlear implantation in auditory neuropathy patients is variable and has yet to be reported in any patients with DDON syndrome. The reported case describes a male initially diagnosed with X-linked agammaglobulinemia due to recurrent infections. Speech, language and hearing were typical of a child in the first year of life; however profound hearing loss developed and cochlear implantation was performed at age 4. Following implantation, further genetic workup determined that the patient carries a deletion that includes BTK and DDP1/TIMM8a, consistent with the diagnosis of X-linked agammaglobulinemia and DDON syndrome. The patient's performance with the cochlear implant was marginal even after 2 years of use, with continued poor scores in standardized speech, language and audiometric tests. Additionally, his most-comfortable-level implant setting requires higher-than-normal current applied to the electrode array. This case report supports other studies showing that DDON syndrome results in an auditory neuropathy. Further investigation is required to determine the efficacy of cochlear implantation in this patient population. DDON syndrome should be considered in patients with X-linked agammaglobulinemia and hearing loss.
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PMID:Cochlear implantation in deafness-dystonia-optic neuronopathy (DDON) syndrome. 1793 19

TLR8 (Toll-like receptor 8) is activated by ssRNAs (single-stranded RNAs) and synthetic imidazoquinoline compounds that resemble purines and have immunostimulatory activity. TLR8 agonists are particularly effective at inducing Th1-polarizing responses from human monocytes and myeloid dendritic cells, with the magnitude of response substantially exceeding that induced by agonists of other TLRs. Mechanisms underlying the remarkable efficacy of TLR8 agonists may include: (i) particularly robust activation of intracellular signalling cascades culminating in nuclear translocation of NF-kappaB (nuclear factor kappaB), (ii) activation of BTK (Bruton's tyrosine kinase), and (iii) the ability of some imidazoquinolines to induce TLR-independent effects via antagonism of adenosine receptors. The strong agonist activities of TLR8 agonists also extend to human neonatal leucocytes, which usually display impaired Th1-polarizing responses to many diverse stimuli including agonists of other TLRs. Their strong Th1-polarizing properties render TLR8 agonists attractive targets of biopharmaceutical development as agents that may induce protective immune responses in diverse populations, including newborns.
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PMID:Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: basic mechanisms and translational opportunities. 1803 Dec 50

Class IA PI3Ks (phosphoinositide 3-kinases) generate the secondary messenger PtdIns(3,4,5)P(3), which plays an important role in many cellular responses. The accumulation of PtdIns(3,4,5)P(3) in cell membranes is routinely measured using GFP (green fluorescent protein)-labelled PH (pleckstrin homology) domains. However, the kinetics of membrane PtdIns(3,4,5)P(3) synthesis and turnover as detected by PH domains have not been validated using an independent method. In the present study, we measured EGF (epidermal growth factor)-stimulated membrane PtdIns(3,4,5)P(3) production using a specific monoclonal anti-PtdIns(3,4,5)P(3) antibody, and compared the results with those obtained using PH-domain-dependent methods. Anti-PtdIns(3,4,5)P(3) staining rapidly accumulated at the leading edge of EGF-stimulated carcinoma cells. PtdIns(3,4,5)P(3) levels were maximal at 1 min, and returned to basal levels by 5 min. In contrast, membrane PtdIns(3,4,5)P(3) production, measured by the membrane translocation of an epitope-tagged (BTK)PH (PH domain of Bruton's tyrosine kinase), remained approx. 2-fold above basal level throughout 4-5 min of EGF stimulation. To determine the reason for this disparity, we measured the rate of PtdIns(3,4,5)P(3) hydrolysis by measuring the decay of the PtdIns(3,4,5)P(3) signal after LY294002 treatment of EGF-stimulated cells. LY294002 abolished anti-PtdIns(3,4,5)P(3) membrane staining within 10 s of treatment, suggesting that PtdIns(3,4,5)P(3) turnover occurs within seconds of synthesis. In contrast, (BTK)PH membrane recruitment, once initiated by EGF, was relatively insensitive to LY294002. These data suggest that sequestration of PtdIns(3,4,5)P(3) by PH domains may affect the apparent kinetics of PtdIns(3,4,5)P(3) accumulation and turnover; consistent with this hypothesis, we found that GRP-1 (general receptor for phosphoinositides 1) PH domains [which, like BTK, are specific for PtdIns(3,4,5)P(3)] inhibit PTEN (phosphatase and tensin homologue deleted on chromosome 10) dephosphorylation of PtdIns(3,4,5)P(3) in vitro. These data suggest that anti-PtdIns(3,4,5)P(3) antibodies are a useful tool to detect localized PtdIns(3,4,5)P(3), and illustrate the importance of using multiple approaches for the estimation of membrane phosphoinositides.
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PMID:Quantification of PtdIns(3,4,5)P(3) dynamics in EGF-stimulated carcinoma cells: a comparison of PH-domain-mediated methods with immunological methods. 1821 45

Most genetic disruptions underlying human disease are microlesions, whereas gross lesions are rare with gross deletions being most frequently found (6%). Similar observations have been made in primary immunodeficiency genes, such as BTK, but for unknown reasons the IGHM and DCLRE1C (Artemis) gene defects frequently represent gross deletions ( approximately 60%). We characterized the gross deletion breakpoints in IGHM-, BTK-, and Artemis-deficient patients. The IGHM deletion breakpoints did not show involvement of recombination signal sequences or immunoglobulin switch regions. Instead, five IGHM, eight BTK, and five unique Artemis breakpoints were located in or near sequences derived from transposable elements (TE). The breakpoints of four out of five disrupted Artemis alleles were located in highly homologous regions, similar to Ig subclass deficiencies and Vh deletion polymorphisms. Nevertheless, these observations suggest a role for TEs in mediating gross deletions. The identified gross deletion breakpoints were mostly located in TE subclasses that were specifically overrepresented in the involved gene as compared to the average in the human genome. This concerned both long (LINE1) and short (Alu, MIR) interspersed elements, as well as LTR retrotransposons (ERV). Furthermore, a high total TE content (>40%) was associated with an increased frequency of gross deletions. Both findings were further investigated and confirmed in a total set of 20 genes disrupted in human disease. Thus, to our knowledge for the first time, we provide evidence that a high TE content, irrespective of the type of element, results in the increased incidence of gross deletions as gene disruption underlying human disease.
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PMID:Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. 1825 13

Further development of haematopoietic stem cell (HSC) gene therapy will depend on enhancement of gene transfer safety: ad hoc improvement of vector design relating to each particular disease is thus a crucial issue for HSC gene therapy. We modified a previously described lentiviral vector by adding the Emumar B-specific enhancer to a human CD19 promoter-derived sequence (Mol Ther 2004;10:45-56). We thus significantly improved the level of expression of the green fluorescent protein (GFP) reporter gene while retaining the specificity of expression in B-cell progeny of transduced human CD34+ progenitor cells obtained from cord blood or adult bone marrow. Indeed, GFP was strongly expressed from early medullary pro-B cells to splenic mature B cells whereas transgene expression remained low in transduced immature progenitors as in myeloid and T-lymphoid progeny retrieved from xenografted NOD/SCID/gammac(null) mice. Using this lentiviral vector, we further demonstrated the possibility to express a functional human BTK protein in long-term human CD34+ cell B-lymphoid progeny. This newly designed lentiviral vector fulfils one of the pre-requisites for the development of efficient and safe gene therapy for X-linked agammaglobulinaemia, the most common primary humoral immunodeficiency disorder.
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PMID:Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. 1832 95

The present study reports on the chromosomal expression and localization of aphidicolin-induced fragile sites in the standard karyotype of river buffalo (Bubalus bubalis, 2n = 50) with the aim of establishing a 'fragile site map' of the species. Totally, 400 aphidicolin-induced breakages were analyzed from eight young and clinically healthy animals, four males and four females; these breakages were localized in 106 RBG-negative chromosome bands or at the band-interband regions. The number of breakages per chromosome did not vary statistically 'among' the animals investigated but the differences among individual chromosomes were highly significant thus indicating that the chromosomal distribution of the breakages is not random and appears only partially related to chromosome length. Fragile sites were statistically determined as those chromosomal bands showing three or more breakages. In the river buffalo karyotype, 51 fragile sites were detected and localized on the standardized ideogram of the species. The most fragile bands were as follows: 9q213 with 24 breakages out of 400; 19q21 with 16, 17q21 and inacXq24 with 15, 15q23 with 13 and 13q23 with 12 breaks, respectively. Previous gene mapping analysis in this species has revealed that the closest loci to these fragile sites contain genes such as RASA1 and CAST (9q214), NPR3 and C9 (19q19), PLP and BTK (Xq24-q25), OarCP09 (15q24), and EDNRB (13q22) whose mutations are responsible for severe phenotypic malformations and immunodeficiency in humans as well as in mice and meat quality in pigs. Further cytogenetic and molecular studies are needed to fully exploit the biological significance of the fragile sites in karyotype evolution of domestic animals and their relationships with productive and reproductive efficiency of livestock.
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PMID:Chromosomal expression and localization of aphidicolin-induced fragile sites in the standard karyotype of river buffalo (Bubalus bubalis). 1846 45

The key role of kinases in signal transduction and cell growth regulation has been a long standing interest among academics and the pharmaceutical industry. Recombinant enzymes have been used to understand the mechanism of action as well as to screen for chemical inhibitors. The baculo-insect system has been the primary method used to obtain soluble and active kinases, usually producing a mixture of the kinase in various phosphorylation states in different conformations. To obtain a homogenous preparation of non-phosphorylated kinases is critical for biochemical, biophysical and kinetic studies aimed at understanding the mechanism of kinase activation. Taking advantage of the eukaryotic expression property of insect cells, we were able to obtain high yield expression of non-phosphorylated protein tyrosine kinases BTK, JAK3 and Eph2A through coexpression with the tyrosine phosphatase YopH, which suggests that this method can be applied to protein tyrosine kinases in general. We have demonstrated that the fully non-phosphorylated BTK obtained with this method is suitable for various biochemical and kinetic studies.
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PMID:High yield expression of non-phosphorylated protein tyrosine kinases in insect cells. 1860 36

BTK deficiency is a primary immunodeficiency disease characterized by the absence of circulating B cells and agammaglobulinemia. While recurrent bacterial infections are the most common manifestations, symptoms of allergy and asthma are rare. We present the case of a 7-year-old boy who presented with asthma symptoms, allergic rhinitis, and severe papular urticaria. He had a positive skin prick test to aeroallergens and food allergens. However, further laboratory tests revealed a low number of B cells and decreased serum levels of all immunoglobulin isotypes. Molecular analysis revealed a mutation in the BTK gene. Although patients with BTK deficiency seem to be protected from atopy, our patient had allergic symptoms suggesting a bias toward a type 2 helper T cell pattern in this case. Primary antibody deficiency should be considered in the differential diagnosis of pediatric allergy and asthma when respiratory infection persists despite appropriate treatment.
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PMID:Asthma and allergic rhinitis in a patient with BTK deficiency. 1871 39

Bruton's tyrosine kinase (Btk) belongs to the Tec family of nonreceptor protein tyrosine kinases. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA); a primary immunodeficiency disorder in human. No clear genotype-phenotype correlation has been established in XLA so far. To determine how differently mutations in BTK affect the severity of the disease and if BTK promoter polymorphic variant or intron 1 polymorphic variant in Tec, a cytoplasmic tyrosine kinase that might substitute for Btk, could contribute to the clinical phenotype, we analyzed the clinical and molecular findings in a cohort of XLA patients. Polymorphisms in BTK promoter and TEC intron 1 regions include substitutions of C>T (rs2071219) and T>C (rs2664019), respectively. Btk expression was evaluated by means of western immunoblotting and fluorescence-activated cell sorter analysis. Mutations were categorized as mild or severe and patients were evaluated for the clinical severity of disease. On the basis of the results, severe genotypes do not necessarily lead to severe phenotypes. More over, in a considerable number of patients with mild phenotype we showed a severe mutation with a tendency toward C substitution in the polymorphic site on TEC intron 1.
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PMID:Genotype-phenotype correlation in Bruton's tyrosine kinase deficiency. 1877 60


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