Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eosinophilia-myalgia syndrome (EMS), a recently described inflammatory disorder characterized by myalgia, peripheral eosinophilia, and multisystem inflammation is associated with L-tryptophan consumption. Fibrosis of various tissues due to excessive accumulation of type I collagen is a prominent late manifestation of the syndrome. 1,1'-Ethylidenebis[L-tryptophan] (EBT), an impurity distinct from L-tryptophan found in case-associated lots, has been implicated in function in vitro. Incubation of confluent fibroblasts with EBT, but not its hydrolysis product 1-methyl-tetrahydro-beta-carboline-3-carboxylic acid, caused a dose-dependent increase in collagen synthesis and in type I collagen mRNA levels independent of its effect on proliferation. In contrast, expression mRNA for fibronectin was not affected. These findings indicate that EBT stimulates type I collagen production by human fibroblast, and suggest that EBT may be involved in the development of fibrosis in EMS.
Biochem Mol Biol Int 1995 Nov
PMID:1,1'-Ethylidenebis[L-tryptophan], an impurity in L-tryptophan associated with eosinophilia-myalgia syndrome, stimulates type I collagen gene expression in human fibroblasts in vitro. 862 99

Cytokines are soluble proteins that are produced and secreted as part of the immune response to a variety of tissue insults including infection, cancer, and autoimmunity. Most cytokines are secreted by cells of the immune system, but some (for example, type I interferons) are released from "nonimmunological" cells such as fibroblasts and epithelial cells. Cytokines have pleiotropic effects, acting on many somatic cell types to modulate the host's immune response. For the most part, cytokines exert their antimicrobial actions locally---they are secreted by cells in the area of infection, and their effects are restricted to neighboring cells. While many of their local effects benefit the host, cytokines are soluble molecules that may act systemically and are often responsible for many of the symptoms of infection (e.g., headache, fever, myalgia). In high concentrations they can be toxic, or even lethal. Human clinical trials involving the systemic injection of purified cytokines such as interleukins 2 and 12 and tumor necrosis factor alpha provide compelling evidence for the toxicity of these molecules. Likewise, studies of septic shock syndrome demonstrate how overproduction/aberrant production of inflammatory cytokines can lead to rapid mortality. The host may attempt to counter high cytokine levels by releasing soluble cytokine receptors (sCR) or by synthesizing high-affinity anti-cytokine antibodies (acAb), and these natural responses have spawned great interest as potential therapeutic approaches for alleviating cytokine-mediated disease. However, recent studies indicate that these in vivo interactions are much more complex than previously realized; administration of sCR or acAb may either inhibit or (paradoxically) enhance cytokine activity. An alternative therapeutic approach is to intervene at the source of cytokine production. T cells initiate cytokine production only upon antigen contact and terminate synthesis almost immediately after this contact is broken. Thus T cells secrete cytokines specifically at sites of infection and do not continuously produce these potentially toxic molecules while migrating through uninfected tissues or the bloodstream. By learning more about the molecular mechanisms involved with on/off regulation of cytokine production we may be able to develop novel therapeutic drugs to protect against cytokine-mediated immunopathology. This review discusses the regulation of cytokine function by sCR and acAb and compares this to the regulatory mechanisms that are associated with antigen-specific cytokine release by T cells.
J Mol Med (Berl) 2000
PMID:Clinical implications of dysregulated cytokine production. 1079 42

Adult-onset carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disease characterized by muscle pain and stiffness with rhabdomyolysis and myoglobinuria in severe cases. Exercise, fasting, viral infection, anesthesia, or extremes in temperature may trigger symptoms. A 54-year-old woman exhibited a 35-year history of progressive weakness and myopathic symptoms. CPT II activity in the patient's lymphoblasts, cultured skin fibroblasts, and skeletal muscle was reduced to 47, 43, and 13% of normal, respectively. Respiratory chain enzymes were also reduced in muscle ranging from 22 to 49% of their respective normal reference means. beta-oxidation enzymes in fibroblasts ranged from 29 to 63% of normal. The patient, her father, and her 26-year-old son were all heterozygous for the R503C mutation. The patient's son has a lifelong history of myopathic symptoms while his grandfather only had mild weakness during childhood. Analysis of the V368I and M647V polymorphisms in the CPT2 gene showed that the mutant allele is linked to 368I and 647M in this family and that the normal allele is linked to 647V in the affected patient and her son, and to 647M in the patient's father. While the variability in CPT2 gene haplotypes may contribute to the phenotypic complexities in this family, it is also possible that an additional gene defect in the transport of mitochondrial proteins contributes to the complex phenotype in the patient. We present biochemical and molecular evidence for vertical transmission of a variable myopathy caused by heterozygosity for a single mutation, R503C, in the CPT2 gene.
Mol Genet Metab 2000 Jun
PMID:A variable myopathy associated with heterozygosity for the R503C mutation in the carnitine palmitoyltransferase II gene. 1087 95

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.
Hum Mol Genet 2000 Sep 22
PMID:Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. 1100 38

We identified a novel nonsense mutation in the carnitine palmitoyltransferase (CPT; EC 2.3.1.21) II gene in a patient with biochemical evidence of CPT II deficiency. The 39-year-old man suffered from the muscle form of CPT II deficiency. Attacks of myalgia and muscle weakness started in childhood and led to renal failure five times. A mild proximal weakness of the lower limbs was left as a residue. Molecular genetic analysis revealed the common S113L mutation on one allele. On the other allele a novel 4-bp deletion starting at codon 515 (515del4) was found leading to frameshift that results in a stop codon 15 codons upstream. Our data further expand the genetic heterogeneity in patients with CPT II deficiency.
Mol Genet Metab 2002 Feb
PMID:A novel nonsense mutation (515del4) in muscle carnitine palmitoyltransferase II deficiency. 1185 39

We report the first splice junction mutation to be described in the carnitine palmitoyltransferase (CPT) 2 gene in a patient with the muscle form of CPT II deficiency. The patient, a 25-year-old man, suffered from attacks of myalgia and muscle weakness in early adult life. There was biochemical evidence of CPT II deficiency. Molecular genetic analysis revealed the common S113L mutation on one allele whilst a novel mutation at the splice donor junction in intron 3 was identified on the other allele. Sequencing of reverse transcription polymerase chain reaction (RT-PCR) products clearly demonstrated that this mutation causes the skipping of exon 3, thus establishing its pathogenic role.
Mol Genet Metab 2003 Jun
PMID:A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency. 1280 43

Active regulation of gene expression in the nervous system plays an important role in the development and/or maintenance of inflammatory pain. MicroRNA (miRNA) negatively regulates gene expression via posttranscriptional or transcriptional inhibition of specific genes. To explore the possible involvement of miRNA in gene regulation during inflammatory pain, we injected complete Freund's adjuvant (CFA) unilaterally into the rat masseter muscle and quantified changes in neuron-specific mature miRNAs in the trigeminal ganglion (TG). Real-time reverse-transcription polymerase chain reaction revealed significant, but differential, downregulation of mature miR-10a, -29a, -98, -99a, -124a, -134, and -183 in the ipsilateral mandibular division (V3) of the TG within 4 hr after CFA. In contrast, levels of tested miRNAs did not change significantly in the contralateral V3 or the ipsilateral ophthalmic and maxillary divisions of the TG from inflamed rats, nor in the ipsilateral V3 of saline-injected animals. The downregulated miRNAs recovered differentially to a level equal to or higher than that in naive animals. Full recovery time varied with miRNA species but was at least 4 days. Expression and downregulation of some miRNAs were further confirmed by in situ hybridization of TG neurons that innervate the inflamed muscle. Although neurons of all sizes expressed these miRNAs, their signals varied between neurons. Our results indicate that miRNA species specific to neurons are quickly regulated following inflammatory muscle pain.
Mol Pain 2007 Jun 08
PMID:Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain. 1755 65

Autoimmune liver disease (ALD) includes a spectrum of diseases which comprises both cholestatic and hepatitic forms: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and the so called "overlap" syndromes where hepatitic and cholestatic damage coexists. All these diseases are characterized by an extremely high heterogeneity of presentation, varying from asymptomatic, acute (as in a subset of AIH) or chronic (with aspecific symptoms such as fatigue and myalgia in AIH or fatigue and pruritus in PBC and PSC). The detection and characterization of non organ specific autoantibodies plays a major role in the diagnostic approach of autoimmune liver disease; anti nuclear reactivities (ANA) and anti smooth muscle antibodies (SMA) mark type 1 AIH, liver kidney microsomal antibody type 1 (LKM1) and liver cytosol type 1 (LC1) are the serological markers of type 2 AIH; antimitochondrial antibodies (AMA) are associated with PBC, while no specific marker is found in PSC, since anticytoplasmic neutrophil antibodies with perinuclear pattern (atypical p-ANCA or p-ANNA) are also detected in a substantial proportion of type 1 AIH cases. Treatment options rely on immunosoppressive therapy (steroids and azathioprine) in AIH and on ursodeoxycholic acid in cholestatic conditions; in all these diseases liver transplantation remains the only therapeutical approach for the end stage of liver disease.
Mol Aspects Med
PMID:Autoimmune liver disease 2007. 1806 56

Systemic autoinflammatory diseases are genetic disorders characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. Among them it is recognized the TNF receptor associated periodic syndrome (TRAPS) caused by mutations in the TNFRSF1A gene and characterized by symptoms such as recurrent high fevers, rash, abdominal pain, arthralgia and myalgia. Recent studies have recognized the potential role of TNFRSF1A mutations in Multiple Sclerosis (MS). Our aim was to investigate the role of TNFRSF1A R92Q gene mutation in a cohort of 90 Argentinean MS patients, where we determined the frequency of the TNFRSF1A R92Q mutation. We also compared autoinflammatory symptoms, MS clinical characteristics and treatment response and tolerability in R92Q carriers and non-carriers. Also, we used a case-control study design to obtain the genotypes of 78 healthy controls and assess the role of this mutation as a risk factor for MS. We found that five patients (5.5%) carried the R92Q mutation, four reported autoinflammatory symptoms previous to MS onset. We found no differences in MS clinical features, treatment response and tolerability between carriers and non-carriers. R92Q mutation was more frequent in MS patients as compared to controls. This increases the risk to develop MS in about 4.5 times. The TNFRSF1A R92Q mutation is a common finding in Argentinean MS patients. This genetic variant might be a risk factor for MS.
Mol Biol Rep 2012 Jan
PMID:TNFRSF1A [corrected] R92Q mutation, autoinflammatory symptoms and multiple sclerosis in a cohort from Argentina. 2156 5

Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n=197), mild statin myopathy (n=163), statin-tolerant controls (n=133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n=392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease-causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology.
Mol Genet Metab
PMID:Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. 2179 85


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