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: UMLS:C0036572 (seizures)
80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mutational analysis of potassium (KCNQ2, KCNQ3), sodium (SCN1A, SCN2A), and chloride (CLCN2) ion channels was performed in three children with typical features of the recently described syndrome of migrating partial seizures in infancy. Mutational analysis was performed by PCR and automatic sequencing. The coding regions, including the exon-intron boundaries, were amplified in the patients using appropriate primers sets. No mutations associated to migrating partial seizures have been found. Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. The same variation has been found in 38 out of 100 control alleles. The identification of the genetic basis of this new epileptic encephalopathy requires further studies that might be enforced by familial cases.
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PMID:Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. 1616 94

Seizure is a form of excessive neuronal excitation and seizure-induced neuronal damage has profound effects on the prognosis of epilepsy. In various seizure models, the inactivation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) occurs during seizure activity preceding neuronal cell death. CaMKII is a multifunctional protein kinase enriched in the brain and involved in various ways the regulation of neuronal activity. CaMKII inactivation during seizure activity may modify neuronal cell survival after seizure. However, the mechanism for CaMKII inactivation and its consequence after seizure recovery remain to be elucidated yet. In the present study, we employed a prolonged seizure model by systemic injection of kainic acid into rats and biochemically examined the activity state of CaMKII. In status epilepticus induced by kainic acid, not only the inactivation of CaMKII in brain homogenate, but also a shift in the distribution of CaMKII protein from the soluble to particulate fraction occurred in both hippocampus and parietal cortex. The particulate CaMKII showed a large decrease in the specific activity and a concurrent large increase in the autophosphorylation ratio at Thr-286 (alpha) and at Thr-287 (beta). In contrast, the soluble CaMKII showed normal or rather decreased specific activity and autophosphorylation ratio. After 24 h of recovery from kainic acid-induced status epilepticus, all such changes had disappeared. On the other hand, the total amount of CaMKII was decreased by 35% in hippocampus and 20% in parietal cortex, but the existing CaMKII was indistinguishable from those of controls in terms of the autonomous activity ratio, specific activity and autophosphorylation ratio. Thus, CaMKII inactivation in kainic acid-induced status epilepticus seems to be derived not from simple degradation of the enzyme, but from the formation of the autophosphorylated, inactivated and sedimentable CaMKII. Such a form of CaMKII may be important during pathological conditions in vivo in preventing excessive CaMKII activation due to Ca2+ overload.
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PMID:A mechanism for the inactivation of Ca2+/calmodulin-dependent protein kinase II during prolonged seizure activity and its consequence after the recovery from seizure activity in rats in vivo. 1663 8

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.
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PMID:Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. 1693 60

The Microtubule-Associated Serine/Threonine Kinase family (MAST1-4, and MAST-like) is characterised by the presence of a serine/threonine kinase domain and a postsynaptic density protein-95/discs large/zona occludens-1 domain (PDZ). This latter domain gives the MAST family the capacity to scaffold its own kinase activity. In the present study we have profiled the mRNA for each member of the MAST family transcripts across various tissues, with particular focus on rodent brain. Reverse-transcriptase polymerase chain reaction (RT-PCR) has shown equivalent patterns of expression for MAST1 and 2 in multiple tissues. Both MAST3 and 4 show more distinct expression in several tissues, and MAST-like appears to be predominantly expressed in heart and testis. In situ hybridisation reveals overlapping expression of MAST1 and 2 in specific brain regions. In contrast, MAST3 shows selective expression in the striatum and cerebral cortex. MAST4 also exhibits distinct expression in oligodendrocytes of white matter containing brain regions. In keeping with previous results, this family member also shows increased expression in the hippocampus following seizure-like activity. Our analysis of MAST family expression provides support for the role of these kinases in a broad range of neural functions.
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PMID:Expression of the MAST family of serine/threonine kinases. 1820 61

A method to evaluate kinase inhibitor action was reported [L. Morgan, S.J. Neame, H. Child, R. Chung, B. Shah, L. Barden, J.M. Staddon, T.R. Patel, Development of a pentylenetetrazole-induced seizure model to evaluate kinase inhibitor efficacy in the central nervous system, Neurosci. Lett. 395 (2006) 143-148]. In this, acute administration of the GABA antagonist pentylenetetrazole triggers seizures through glutamate-dependent pathways. Under such conditions, activation of the c-Jun N-terminal kinase (JNK) pathway was detected in hippocampal extracts. Phosphorylation of the upstream JNK kinase MKK4 was also revealed through use of a phospho-MKK4-specific antibody. Here, this antibody is shown to also react with a protein of approximately 125 kDa which underwent increased phosphorylation in response to pentylenetetrazole treatment. The present study aimed to identify the approximately 125 kDa protein as it may provide novel insight into signalling, neuronal activity and seizures. Using chromatographic methods and mass spectrometry, the protein was identified as amphiphysin I. This was confirmed by 2D gel analysis and immunoblot with amphiphysin I-specific antibodies. Although the phospho-MKK4 antibody was raised against an MKK4-specific peptide, partial sequence homology between this sequence and a region of amphiphysin was discerned. New antibodies raised against the phospho-threonine 260-amphiphysin-specific sequence detected increased phosphorylation in response to pentylenetetrazole treatment. This particular phosphorylation site does not seem to have been described before, possibly reflecting a novel regulatory aspect of amphiphysin biology. As amphiphysin is involved in the regulation of endocytosis, phosphorylation at this site may play a role in the regulated re-uptake of synaptic vesicles after neurotransmitter release.
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PMID:Amphiphysin I phosphorylation on residue threonine 260 in a pentylenetetrazole-induced seizure model. 1876 Oct 55

The serine/threonine protein phosphatases are targeted to specific subcellular locations and substrates in part via interactions with a wide variety of regulatory proteins. Understanding these interactions is thus critical to understanding phosphatase function. Using an iterative affinity purification/mass spectrometry approach, we generated a high density interaction map surrounding the protein phosphatase 2A catalytic subunit. This approach recapitulated the assembly of the PP2A catalytic subunit into many different trimeric complexes but also revealed several new protein-protein interactions. Here we define a novel large multiprotein assembly, referred to as the striatin-interacting phosphatase and kinase (STRIPAK) complex. STRIPAK contains the PP2A catalytic (PP2Ac) and scaffolding (PP2A A) subunits, the striatins (PP2A regulatory B''' subunits), the striatin-associated protein Mob3, the novel proteins STRIP1 and STRIP2 (formerly FAM40A and FAM40B), the cerebral cavernous malformation 3 (CCM3) protein, and members of the germinal center kinase III family of Ste20 kinases. Although the function of the CCM3 protein is unknown, the CCM3 gene is mutated in familial cerebral cavernous malformations, a condition associated with seizures and strokes. Our proteomics survey indicates that a large portion of the CCM3 protein resides within the STRIPAK complex, opening the way for further studies of CCM3 biology. The STRIPAK assembly establishes mutually exclusive interactions with either the CTTNBP2 proteins (which interact with the cytoskeletal protein cortactin) or a second subcomplex consisting of the sarcolemmal membrane-associated protein (SLMAP) and the related coiled-coil proteins suppressor of IKKepsilon (SIKE) and FGFR1OP2. We have thus identified several novel PP2A-containing protein complexes, including a large assembly linking kinases and phosphatases to a gene mutated in human disease.
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PMID:A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. 1878 53

The use of low-frequency stimulation (LFS) as a therapy for epilepsy is currently being studied in experimental animals and patients with epilepsy. In the present study, the role of serine/threonine protein phosphatases in the inhibitory effects of LFS on perforant path kindling acquisition was investigated in rats. Animals were kindled by stimulation of perforant path in a stimulation using rapid kindling procedure (six stimulations per day). LFS (1Hz) was applied immediately after termination of each kindling stimulation. FK506 (1microM; i.c.v.), a serine/threonine protein phosphatase PP2B inhibitor and okadaic acid (1microM; i.c.v.), a serine/threonine protein phosphatases PP1/2A inhibitor, were daily microinjected into the left ventricle 10min before starting the stimulation protocol. Application of LFS retarded the kindling acquisition and delayed the expression of different kindled seizure stages significantly. In addition, LFS reduced the increment of daily afterdischarge duration during kindling development. Neither FK506 nor okadaic acid microinjection interfere with the antiepileptogenic effect of LFS on kindling parameters. Obtained results showed that activation of PP1/2A and PP2B, which play a critical role in LFS induced down-regulation of synaptic strength, had no role in mediating the inhibitory effects of LFS on perforant path kindling acquisition.
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PMID:Serine/threonine protein phosphatases have no role in the inhibitory effects of low-frequency stimulation in perforant path kindling acquisition in rats. 1915 Mar 91

Cerebral cavernous malformations (CCMs) may cause recurrent headaches, seizures, and hemorrhagic stroke and have been associated with loss-of-function mutations in CCM1/KRIT1, CCM2, and CCM3/programmed cell death 10 (PDCD10). The CCM3/PDCD10 amino acid sequence does not reveal significant homologies to protein domains with known structure. With the help of the only published human in-frame deletion of the CCM3 gene (c.97-?_150+?del), CCM3:p.L33_K50del, we have identified the interaction domain of CCM3 with the oxidant stress response serine/threonine kinase 25 (STK25, YSK1, SOK1) and with the mammalian Ste20-like kinase 4 (MST4, MASK). Consistently, nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analyses revealed two STK25 phosphorylation sites at serine 39 and threonine 43. The corresponding in-frame deletion of zebrafish ccm3a, dccm3:p.L31_K48del, also resulted in impaired interaction with STK25 and MST4. In agreement with the observed redundant biochemical functionality of zebrafish ccm3a and its duplicate ccm3b, simultaneous inactivation of both genes resulted in a progressive cardiovascular phenotype in zebrafish indistinguishable from ccm1 and ccm2 mutants. The pronounced cardiovascular dilatations could be recapitulated by morpholino-induced in-frame skipping of the exon encoding the STK25 and MST4 binding site of zebrafish Ccm3a if Ccm3b was repressed in parallel. Using a novel zebrafish model of CCM, we could thus demonstrate that the newly mapped STK25 and MST4 interaction domain within the CCM3 protein plays a crucial role for vascular development in zebrafish.
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PMID:Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein. 1947 55

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle defect. While hemizygous males typically present with hyperammonemic coma in infancy, reports of rare late-onset presentations exist, with poor outcomes in males up to 58 years old. Relatives with mutations identical to affected patients often remain asymptomatic, and it is likely that environmental and genetic factors influence disease penetrance and expression. Here, we present our investigation of a patient with late-onset presentation, and we emphasize the potential role of environmental and genetic factors on disease expression. The patient was a previously healthy 62-year-old man who developed mental slowing, refractory seizures, and coma over an 8-day period. Interestingly, the patient had recently used home gardening fertilizers and pesticides. Evaluations for drug and alcohol use, infections, and liver disease were negative. Despite aggressive therapy, blood NH(3) concentration peaked at 2,050 muM and the patient died from cerebral edema and cerebellar herniation. Analysis of the OTC gene showed a Pro-225-Thr (P225T) change in exon 7, a mutation that has been previously implicated in OTC deficiency. This case illustrates that OTC deficiency can cause acute, severe hyperammonemia in a previously healthy adult and that the P225T mutation can be associated with late-onset OTC deficiency. We speculate that exposure to organic chemicals might have contributed to the onset of symptoms in this patient. This case also emphasizes that persistent hyperammonemia may cause irreversible neurologic damage and that after the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle disorders and other causes of hyperammonemic encephalopathy.
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PMID:Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male. 1966 72

Postictal movement dysfunction is a common symptom in patients with epilepsy. We investigated the involvement of opioid receptors in the nucleus accumbens (NAC) in amygdaloid kindling-induced postictal decrease in locomotion (PDL) in rats. Seizures were induced by daily electrical stimulation of the basolateral amygdala until four consecutive stage 5 seizures were elicited. Locomotion was quantified before and after infusion of an opioid receptor antagonist or saline into the NAC. Whereas PDL was induced after a stage 5 seizure in saline-infused rats, pre-infusion of the mu opioid receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP, 5 microg/1 microL/side) into the NAC prevented PDL. Pre-infusion of delta (naltrindole, 30 microg/1 microL/side), kappa (nor-binaltorphimine, 1.8 microg/1 microL/side), or nonselective (naloxone, 10 microg/1 microL/side) opioid receptor antagonists did not block PDL, but late postictal hyperactivity was blocked by naltrindole. None of the antagonists affected amygdaloid evoked afterdischarge duration. It is suggested that mu opioid receptors in the NAC participate in amygdaloid seizure-induced PDL without affecting seizure duration.
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PMID:Nucleus accumbens mu opioid receptors mediate immediate postictal decrease in locomotion after an amygdaloid kindled seizure in rats. 2011 38


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