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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic studies of autism spectrum conditions (ASC) have mostly focused on the "low functioning" severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a "high-functioning" subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping.
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PMID:Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. 1959 35

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease characterized by anhidrosis, insensitivity to noxious stimuli, and mental retardation. Mutations in the NTRK1 gene are associated with the pathogenesis of CIPA. In this study, we performed a clinical and genetic analysis on the NTRK1 gene in four Korean patients with CIPA. All patients had typical clinical manifestations of CIPA, including anhidrosis, recurrent fever, absent pain perception, and developmental delay. Sequencing analysis revealed one predominant mutation, c.851-33T>A, in four affected alleles and three novel mutations, including c.287+2dupT, c.2155G>A (p.Glu719Lys), and c.1218delC (p.Pro407ArgfsX), in each affected allele. For one patient, who was heterozygous for c.851-33T>A, another mutation could not be identified, suggesting that a possible hidden intronic or large genomic mutation may have been present. This study extends the spectrum of mutations in the NTRK1 gene and confirms that Korean patients with CIPA have the same genetic background as other ethnicities.
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PMID:Clinical and genetic analysis of Korean patients with congenital insensitivity to pain with anhidrosis. 1961 35

In recent years, significant progress has been made in elucidating the genetic bases promoting tumorigenesis in various human neoplasms. Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is a major event in the carcinogenesis of papillary thyroid carcinoma (PTC), the most prevalent endocrine malignancy. Affected elements include RET/PTC rearrangements and point mutations of the Ras and BRAF genes. Mutations in these genes are found in over 70% of PTC. Chromosomal RET rearrangements, called RET/PTC, result in constitutive ligand-independent activation of RET kinase, which was the first genetic anomaly detected in PTC and is found in 5-70% of tumoral samples. Although less frequent, the activation of other tyrosine kinase receptors, such as NTRK1, c-Met or EGFR, has also been reported in PTC. The BRAF mutation represents the most common genetic alteration found in PTC. More than 90% of BRAF mutations lead to a change of a valine to a glutamic acid at position 600 (V600E). Finally, Ras is the least affected molecule in the pathway. A relationship between clinical behavior and these genetic alterations has been proposed. Thus, the BRAF mutation is associated with a more aggressive PTC phenotype and is correlated with poorer outcomes. However, no clear association has been found between RET/PTC and clinical features. The discovery of these alterations opens the way to new therapeutic strategies, especially to treat those patients in whom conventional therapy is not effective. Several new drugs are being tested, such as small molecule tyrosine kinase inhibitors. Some of these recently developed agents have begun to be used with promising results.
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PMID:[The mitogen-activated protein kinase (MAPK) signaling pathway in papillary thyroid cancer. From the molecular bases to clinical practice]. 1962 34

We investigated protein abundance in order to differentiate radiation-associated papillary thyroid cancers (PTC) from other etiologies for e.g. forensic purposes. Proteins were extracted from frozen tissues originating from 91 sporadic PTCs and 86 post-Chernobyl PTCs. Proteins were separated gel-electrophoretically, gels were silver stained, spots scanned and their intensity quantified. After excision of spots from the gel and protein digestion, MALDI-TOF mass spectrometry was performed followed by correlation of these results to human proteins using appropriate software and database. After this screening approach, altogether 20 candidate proteins were selected and measured semiquantitatively (Remmele score) using immunohistochemistry. Logistic regression modeling was performed for discriminating the groups. NTRK1, metalloproteinases (MMP-1, MMP-9 and MMP-13) and Cathepsins (-W and -X) proved to be of highest significance for discriminating the groups irrespective of the regression model utilized. When considering age and gender, each of 3 proteins by itself made possible a complete separation of the groups otherwise a combination of 2 of the 5 proteins mentioned was needed. In conclusion, abundance of proteins known to be associated with a more aggressive tumor type (MMPs and Cathepsins) appeared increased in post-Chernobyl PTC compared to sporadic PTC, thus underlining the known aggressiveness of radiation-associated PTC. These proteins make it possible to completely distinguish post-Chernobyl from sporadic PTC using routine immunohistology.
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PMID:Sporadic and radiation-associated papillary thyroid cancers can be distinguished using routine immunohistochemistry. 1963 89

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.
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PMID:Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. 1965 2

Thyroid cancer, and its most common type, papillary carcinoma, frequently have chromosomal rearrangements and therefore represent a good model for the understanding of mechanisms of chromosomal rearrangements in solid tumors. Several types of rearrangement known to occur in thyroid cancer, including RET/PTC, NTRK1 and BRAF/AKAP9, are more common in radiation-associated thyroid tumors and RET/PTC can be induced experimentally by exposing human thyroid cells to ionizing radiation. In this review, the molecular mechanisms of generation of RET/PTC and other chromosomal rearrangements are discussed, with the emphasis on the role of nuclear architecture and interphase gene proximity in the generation of intrachromosomal rearrangements in thyroid cells.
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PMID:Mechanisms of chromosomal rearrangements in solid tumors: the model of papillary thyroid carcinoma. 1976 98

TRK oncogenes are observed in a consistent fraction of papillary thyroid carcinoma (PTC); they arise from the fusion of the 3' terminal sequences of the NTRK1/NGF receptor gene with 5' terminal sequences of various activating genes, such as TPM3, TPR and TFG. TRK oncoproteins display constitutive tyrosine-kinase activity, leading to in vitro and in vivo transformation. In this review studies performed during the last 20 years will be summarized. The following topics will be illustrated: (a) frequency of TRK oncogenes and correlation with radiation and tumor histopathological features; (b) molecular mechanisms underlying NTRK1 oncogenic rearrangements; (c) molecular and biochemical characterization of TRK oncoproteins, and their mechanism of action; (d) role of activating sequences in the activation of TRK oncoproteins.
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PMID:Rearrangements of NTRK1 gene in papillary thyroid carcinoma. 1988 30

Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, RET and neurotrophic tyrosine kinase receptor type I (NTRK1) by intra- and interchromosomal rearrangements has been suggested as a cause of the disease. However, many phenotypically similar tumors do not carry an activated RET or NTRK-1 gene or express abnormal ret or NTRK-1 transcripts. Thus, we hypothesize that other cellular RTK-type genes are aberrantly expressed in these tumors. Using fluorescence in situ hybridization-based methods, we are studying karyotype changes in a relatively rare subgroup of PTCs, i.e., tumors that arose in children following the 1986 nuclear accident in Chernobyl, Ukraine. Here, we report our technical developments and progress in deciphering complex chromosome aberrations in case S48TK, an aggressively growing PTC cell line, which shows an unusual high number of unbalanced translocations.
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PMID:BAC-FISH assays delineate complex chromosomal rearrangements in a case of post-Chernobyl childhood thyroid cancer. 1999 98

Structural chromosome aberrations are known hallmarks of many solid tumors. In the papillary form of thyroid cancer (PTC), for example, activation of the receptor tyrosine kinase (RTK) genes, ret or the neurotrophic tyrosine kinase receptor type I (NTRK1) by intra- or interchromosomal rearrangements have been suggested as a cause of the disease. The 1986 accident at the nuclear power plant in Chernobyl, Ukraine, led to the uncontrolled release of high levels of radioisotopes. Ten years later, the incidence of childhood papillary thyroid cancer (chPTC) near Chernobyl had risen by two orders of magnitude. Tumors removed from some of these patients showed aberrant expression of the ret RTK gene due to a ret/PTC1 or ret/PTC3 rearrangement involving chromosome 10. However, many cultured chPTC cells show a normal G-banded karyotype and no ret rearrangement. We hypothesize that the "ret-negative" tumors inappropriately express a different oncogene or have lost function of a tumor suppressor as a result of chromosomal rearrangements, and decided to apply molecular and cytogenetic methods to search for potentially oncogenic chromosomal rearrangements in Chernobyl chPTC cases. Knowledge of the kind of genetic alterations may facilitate the early detection and staging of chPTC as well as provide guidance for therapeutic intervention.
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PMID:Kinase expression and chromosomal rearrangements in papillary thyroid cancer tissues: investigations at the molecular and microscopic levels. 2008 51

Mutations of the neurotrophin receptor tyrosine kinase TrkA (NTRK1) cause congenital sensory neuropathy with insensitivity to pain and anhydrosis (CIPA), also called hereditary sensory and autonomous neuropathy type IV (HSAN IV). The neuronal splice variant of TrkA, TrkAII, binds two neurotrophin ligands, nerve growth factor (NGF) and neurotrophin-3 (NT3). Several studies have demonstrated NGF signaling defects in CIPA-associated TrkA mutants. To date, however, no study has examined NT3/TrkA signaling of CIPA mutants. As the interaction of NT3 and TrkA temporally and spatially precedes the interaction of NGF with TrkA, we examined the signaling of NT3 in a CIPA-associated TrkA mutant. Intriguingly, we revealed remarkable defects in NT3-induced ERK1/2 phosphorylation and neurite outgrowth. The impact of our findings is twofold. First, our data call for a re-examination of previously described TrkAII CIPA mutants regarding their NT3 signaling capability. Second, we envision that CIPA/HSAN IV polyneuropathies might fall into two different subgroups: one with diminished NT3/TrkAII signaling, in which axons actually do not reach their targets, and a second group with sufficient NT3/TrkAII signaling but diminished NGF/TrkAII signaling, in which axons do reach their targets, yet degenerate after successful target engagement.
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PMID:Impaired neurotrophin-3 signaling in a TrkAII mutant associated with hereditary polyneuropathy. 2018 29


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