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)

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system.
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PMID:Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. 869 25

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

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

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.
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PMID:No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V. 1260 14

We report on a 10-year-old girl with anhidrosis and insensibility to pain, but no severe mental retardation or self-mutilation, diagnosed as hereditary sensory and autonomic neuropathy type IV (HSAN IV). Genetic analysis of her TRKA gene, which is responsible for HSAN IV, revealed two novel missense mutations in the tyrosine kinase domain. Cardiovascular autonomic nervous system function tests showed normal muscle sympathetic nerve activity associated with arterial baroreflex, reduced skin sympathetic nerve activity in the second and fifth fingers and palms, and abnormal circadian rhythm of cardiovascular autonomic nervous system. These findings have never before been reported in HSAN IV and may provide a clue to the neurological pathophysiology of this disease.
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PMID:The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene. 1553 59

Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a severe autosomal recessive disorder characterized by childhood onset of sensory and autonomic dysfunction leading to hyperthermia, recurrent infections and physical impairment due to complications of osteoarthritis. Cognitive impairment and aggressive behaviour is common. HSAN4 is caused by mutations in the NTRK1 gene coding for the tyrosine kinase receptor A. We present detailed description of a rare, mild HSAN4 phenotype associated with two novel NTRK1 mutations. This Swedish patient presents with an adult onset of painful Charcot arthropathy, prolonged wound healing, discrete polyneuropathy, hypohidrosis without further autonomic dysfunction and no cognitive affection.
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PMID:Expanded HSAN4 phenotype associated with two novel mutations in NTRK1. 1865 23

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

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a very rare autosomal recessive disorder characterized by recurrent episodes of unexplained fever, extensive anhidrosis, total insensitivity to pain, hypotonia, and mental retardation. The absence of urticarial reaction to intradermal injection of histamine is a sign of great diagnostic value, but this is common to all types of HSAN. The most frequent complications of this disease are corneal scarring, multiple fractures, joint deformities, osteomyelitis, and disabling self-mutilations. Malignant hyperthermia and sepsis are major causes of mortality. We relate the first observations of two Tunisian children with genetically confirmed HSAN IV. Our goal is to review the clinical aspects of this mysterious neuropathy and to emphasize the peculiarities of its management. These two patients are brothers from 1st-degree consanguineous parents (cousins) with no particular medical history. The 1st patient, the family's 1st child, presented in the 1st h of life with hypotonia and persistent fever, which was refractory to antipyretics. At the age of 8 months, the patient presented recurrent febrile seizures and developed significant self-mutilations of the fingers and tongue. He died 3 months later in a context of multivisceral failure from sepsis and malignant hyperthermia. The 2nd patient, currently aged 4 years, was born after a normal sister. He consulted in the neonatal period for a high fever. The diagnosis of HSAN IV was rapidly suspected and genetically confirmed. In fact, this patient is homozygous for the NTRK1 gene, whereas his sister and both parents are heterozygous. Special predispositions have been taken to improve the course of the disease such as air conditioning to control hyperthermia, a dental tray to reduce the injuries resulting from self-mutilation, regular moistening of the eyes to avoid corneal drying, and chlorpromazine to control hyperactivity and reduce injuries. The good progression with all these predispositions and others underlines the importance of appropriate multidisciplinary management and close monitoring of patients suffering from HSAN IV, especially during the first 3 years of life. Indeed, mortality, behavioral disorders, and mental retardation significantly decrease after this age. New curative treatments are expected in the next decade.
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PMID:[Hereditary sensory and autonomic neuropathy type IV: a report on two cases]. 2139 70

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is a rare autosomal recessive disorder characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, and mental retardation. It is caused by mutations in the gene coding for neurotrophic tyrosine kinase receptor type 1 (NTRK1; MIM# 191315). We screened two Chinese CIPA cases for mutations in the NTRK1 gene and examined their phenotype. Two novel mutations of the NTRK1 gene and two known mutations were identified. Including our two novel mutations, there are now 62 different NTRK1 gene mutations reported in patients with CIPA. We find that a combination of two null alleles usually leads to the severe phenotype, while the mild form of the CIPA disease is associated with at least one mild allele. Thirty-four among the 62 mutations (55%) are located within the tyrosine kinase domain of the NTRK1 protein. We concluded that the tyrosine kinase domain is a hot spot for mutations.
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PMID:Novel nonsense and frameshift NTRK1 gene mutations in Chinese patients with congenital insensitivity to pain with anhidrosis. 2265 42


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