Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Point mutations affecting the NTRK1/TRKA gene, encoding one of the receptors for the nerve growth factor (NGF), have been detected in congenital insensitivity to pain with anhidrosis (CIPA), a human hereditary sensory neuropathy characterized by absence of reaction to noxious stimuli and anhidrosis. To define the defect of NTRK1 in CIPA patients, we have introduced one of the previously reported mutations (Gly571Arg) into both the NTRK1 and the TRK-T3 oncogene cDNAs. The expression of the mutated constructs into COS1 cells revealed that the introduced mutation, while not affecting its correct membrane localization, rendered the NTRK1 protein unable to undergo activation upon stimulation with NGF. Similarly, the mutation abolished the constitutive activation of the TRK-T3 oncogene. Transfection into NIH3T3 and PC12 cells showed the loss of transforming and differentiating activity by the mutated constructs. Our results demonstrate clearly that the CIPA mutations cause the inactivation of the NTRK1 receptor, thus exerting a loss of function effect, and provide an experimental approach to distinguish functional mutations from genetic polymorphisms.
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PMID:The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. 1056 24

Rearrangements of NTRK1 proto-oncogene were detected in 'spontaneous' papillary thyroid carcinomas with a frequency varying from 5 to 25% in different studies. These rearrangements result in the formation of chimaeric genes composed of the tyrosine kinase domain of NTRK1 fused to 5' sequences of different genes. To investigate if the NTRK1 gene plays a role in radiation-induced thyroid carcinogenesis, we looked for the presence of NTRK1-activating rearrangements in 32 human thyroid tumours (16 follicular adenomas, 14 papillary carcinomas and two lymph-node metastases of papillary thyroid carcinomas) from patients who had received external radiation, using the reverse transcription polymerase chain reaction, Southern blot and direct sequencing techniques. These data were compared with those obtained in a series of 28 'spontaneous' benign and malignant thyroid tumours, collected from patients without a history of radiation exposure and four in vitro culture cell lines derived from 'spontaneous' thyroid cancers. Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas. All the radiation-associated adenomas were negative. In the 'spontaneous' tumours, only one of the 14 papillary carcinomas and one of the four in vitro culture cell lines, derived from a papillary carcinoma, presented a NTRK1 rearrangement also with the TPM3 gene. Twenty-five of this series of radiation-associated tumours were previously studied for the ras and RET/PTC oncogenes. In conclusion, our data: (a) show that the overall frequency of NTRK1 rearrangements is similar between radiation-associated (2/31: 6%) and 'spontaneous' epithelial thyroid tumours (2/32: 6%). The frequency, if we consider exclusively the papillary carcinomas, is in both cases 12%; (b) show that the TRK oncogene plays a role in the development of a minority of radiation-associated papillary thyroid carcinomas but not in adenomas; and (c) confirm that RET/PTC rearrangements are the major genetic alteration associated with ionizing radiation-induced thyroid tumorigenesis.
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PMID:Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation. 1064 82

Molecular genetic aberrations and the related phenotypes were investigated in 191 papillary thyroid carcinomas (PTCs) from patients exposed at young age to radioiodine released from the Chernobyl reactor. A high prevalence of RET gene rearrangements (62.3%) with a significant predominance of ELE1/RET (PTC3) over H4/RET (PTC1) rearrangements was found in PTCs of the first post-Chernobyl decade. NTRK1 rearrangements were rare (3.3%). In 3.3%, we observed novel types of RET rearrangements: GOLGA5/ RET (PTC5), HTIF/RET (PTC6), RFG7/RET (PTC7), and an as yet undefined RFGX/RET.RET rearrangements, preferentially ELE1/RET, are related to rapid tumor development. At longer intervals after exposure to ionizing radiation, the prevalence of RET rearrangements declines with a shift from ELE1/RET to H4/RET, most significantly in female patients. The prevalence of specific types of rearrangements is independent of age at irradiation. A significantly higher prevalence of ELE1/RET was observed in the most heavily contaminated Oblasts, Gomel and Brest, suggesting a preferential formation of this type of rearrangement after high thyroid doses. RET rearrangement is related to aggressive growth: Rearrangement-positive PTCs were in a more advanced pT category and more frequently in the pN1 category at presentation than rearrangement-negative PTCs. ELE1/RET is related to the solid variant of PTC, H4/RET more frequently to typical papillary structures. The genotype/phenotype evaluation of post-Chernobyl PTCs reveals a characteristic spectrum of gene rearrangements that lead to typical phenotypes with important biological and clinical implications.
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PMID:Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. 1074 39

Genetic analysis of human papillary thyroid carcinomas (PTC) has revealed unique chromosomal translocations that form oncogenic fusion proteins and promote thyroid tumorigenesis in up to 60% of tumors examined. Although, the majority of thyroid specific translocations involve the growth factor receptor c-RET, variant rearrangements of the receptor for nerve growth factor, NTRK1 have also been described. One such translocation, TRK-T1, forms a fusion protein composed of the carboxyl terminal tyrosine kinase domain of NTRK1 and the amino terminal portion of TPR (Translocated Promoter Region). To determine if TRK-T1 expression can cause thyroid cancer in vivo, we developed transgenic mice that express the human TRK-T1 fusion protein in the thyroid. Immunohistochemical analysis of TRK-T1 transgenic mouse thyroids revealed TRK-T1 staining within the thyroid follicular epithelium. In contrast to nontransgenic littermates, 54% of transgenic mice developed thyroid abnormalities that included follicular hyperplasia and papillary carcinoma. Furthermore, all transgenic mice examined greater than 7 months of age developed thyroid hyperplasia and/or carcinoma. These data support the conclusion that TRK-T1 is oncogenic in vivo and contributes to the neoplastic transformation of the thyroid.
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PMID:The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. 1112 59

Congenital insensitivity to pain with anhidrosis (CIPA), also called hereditary sensory and autonomic neuropathy type IV (HSAN IV), is caused by mutations of the NTRK1 gene coding for the neurotrophic tyrosine kinase receptor type 1. We report the results of the NTRK1 sequence analysis in a CIPA family from Poland. We found that the patient was in a state of compound heterozygosity. He had one mutant allele with a novel G>A substitution in the conserved splice junction donor site affecting the first base pair of intron 5 (IVS5+1G>A). In the other allele he had a cluster of four single nucleotide substitutions in exon 15: an 1876C>T change (relative to the transcription start site) and three G>T changes (1904G>T, 1909G>T and 1915G>T). All of these mutations change the sense of the codons: H598Y, G607V, E609X and V611L, respectively. Mutations E609X and V611L are novel and unique to the patient family and at least one of them, which creates a premature stop codon in position 609, should have a deleterious effect on the gene function. The other two substitutions H598Y and G607V are most likely rare polymorphisms, which are in linkage disequilibrium. They occur together with an estimated allele frequency of about 6%. Our report increases the spectrum of NTRK1 mutations in CIPA patients and describes an unusual case of a cluster of four mutations located close to each other in one exon.
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PMID:Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: a splice junction mutation in intron 5 and cluster of four mutations in exon 15. 1113 46

Human TRKA (NTRK1) encodes the receptor tyrosine kinases (RTKs) for nerve growth factor (NGF) and is the gene responsible for congenital insensitivity to pain with anhidrosis (CIPA), an autosomal recessive disorder characterized by a lack of pain sensation and anhidrosis. We reported 11 putative missense mutations in 31 CIPA families from various ethnic groups. Here we have introduced the corresponding mutations into the TRKA cDNA and examined NGF-stimulated autophosphorylation. We find that wild-type TRKA precursor proteins in a neuronal and a non-neuronal cell line were differentially processed and phosphorylated in an NGF-dependent and -independent manner, respectively. Two mutants (L93P and L213P) in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutants (G516R, G571R, R643W, R648C and G708S) in the tyrosine kinase domain were processed as wild-type TRKA but showed significantly diminished autophosphorylation in both neuronal and non-neuronal cells. In contrast, R85S and (H598Y; G607V), detected previously as double and triple mutations, are probably polymorphisms in a particular ethnic background. The other putative mutant D668Y might be a rare polymorphism or might impair the function of TRKA without compromising autophosphorylation. Mutated residues in the tyrosine kinase domain are conserved in various RTKs and probably contribute to critical function of these proteins. Thus, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. Our data may aid in developing a drug which targets the clinically devastating 'complex regional pain syndrome'.
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PMID:Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. 1115 35

The TRK protooncogene (NTRK1) encodes a cell-surface transmembrane tyrosine kinase (TK) acting as a receptor for nerve growth factor. Oncogenic potential in thyrocytes results from replacing the 5' portion by regulatory parts of other genes, leading to constitutive TK expression. In Italy, human papillary thyroid carcinoma (PTC) shows a frequent activation (50%) of the TK receptor genes NTRK1 and RET. Both genes undergo oncogenic rearrangements by the same mechanism. We previously reported high frequency (6/11) of rearrangement of the RET protooncogene in Chinese PTCs. Wide differences in the frequency (0-10.9%) of the NTRK1 rearrangement in PTCs have been reported in different populations. To investigate the frequency of TRK protooncogene rearrangement in Chinese thyroid tumors, we performed reverse transcriptase polymerase chain reaction to amplify specific TRK rearrangement transcripts. We examined thyroid tumors of 40 patients, including 14 papillary carcinomas, 4 follicular carcinomas, 1 Hurthle cell carcinoma, 1 insular carcinoma, and 20 nodular goiters. NF874 NIH3T3, NF723 NIH3T3, NF861 NIH3T3, and NF881 NIH3T3 were used as controls for TRK-T3, TRK-T2, TRK-T1, and TRK, respectively. No known TRK protooncogene rearrangements were detected among the 40 thyroid tumors in our studies. We suggest that the TK receptor NTRK1 activation seems less important than RET activation in PTCs in the Chinese population.
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PMID:Low frequency of rearrangement of TRK protooncogene in Chinese thyroid tumors. 1121 46

Somatic mutations in the proto-oncogene RET are found in 25% to 80% of sporadic medullary thyroid carcinomas (MTCs). The significance of somatic RET mutation in MTC initiation and progression, however, remains unknown. Like RET, TRK is a neurotrophic receptor tyrosine kinase. Immunostaining has shown that only a subset of normal C cells expresses Trk family receptors, but in C-cell hyperplasia, they consistently express NTRK2, with variable expression of NTRK1 and NTRK3. In later stages of MTC, NTRK2 expression was reduced while NTRK3 expression was increased. In the context of these data, we sought to determine whether sequence variants in NTRK2 and NTRK3 are responsible for these differences in protein expression. We determined the genomic structure of NTRK2 and found that it consists of at least 17 exons varying in size from 36 to 306 bp. Mutation analysis of sporadic MTC did not reveal any sequence variants in NTRK2 but did reveal 3 variants in NTRK3, c.573C >T (N191N, exon 5), c.678T > C (N226N, exon 6) and c.1488C > G (A496A, exon 12) occurring among 19 chromosomes (31%), 1 chromosome (2%) and 24 chromosomes (39%), respectively. Corresponding germline also harbored these variants. There was a trend toward excess association of the NTRK3 variant c.1488C > G (A496A) in cases (24/62 chromosomes, 39%) compared to controls (18/62, 29%), but this difference did not reach significance (p > 0.05). The remaining 2 NTRK3 variants occurred with similar frequencies between MTC cases and population-matched controls (19 vs. 17 and 1 vs. 0, p > 0.05). We conclude that sequence variants in NTRK2 and NTRK3 are not likely to be responsible for large differences in expression at the protein level, but we cannot exclude very low penetrance effects.
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PMID:Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants. 1127 8

A boy with recurrent pyrexial episodes from early life sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons, the pattern of type V hereditary sensory and autonomic neuropathy (HSAN V). DNA analysis showed that he was homozygous for a mutation in the NTRK1/high-affinity nerve growth factor (TrkA) gene, his parents being heterozygous. Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic.
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PMID:A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. 1131 Jun 31

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we developed a comprehensive strategy to screen for TRKA mutations and polymorphisms, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries. Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient. All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder.
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PMID:Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency. 1166 14


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