Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Invest ; 131(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33141761

RESUMO

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs, and therefore, they may represent potential therapeutic drug targets. Using quantitative PCR (qPCR) and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE) and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid-kindling rat model and in the intrahippocampal kainic acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression were persistently dysregulated in the hippocampus compared with in controls. IPR-179 treatment reduced seizure severity in the rapid-kindling model and reduced the number of spontaneous seizures in the kainic acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 exhibits antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials.


Assuntos
Encéfalo/enzimologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Encéfalo/patologia , Epilepsia do Lobo Temporal/enzimologia , Epilepsia do Lobo Temporal/patologia , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/enzimologia , Estado Epiléptico/patologia
2.
Epilepsia ; 61(12): 2836-2846, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33104247

RESUMO

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) is a secreted transsynaptic protein that interacts presynaptically with Kv1.1 potassium channels and a disintegrin and metalloprotease (ADAM) protein 23, and postsynaptically influences α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors through a direct link with the ADAM22 cell adhesion protein. Haploinsufficiency of LGI1 or autoantibodies directed against LGI1 are associated with human epilepsy, generating the hypothesis that a subacute reduction of LGI1 is sufficient to increase network excitability. METHODS: We tested this hypothesis in ex vivo hippocampal slices and in neuronal cultures, by subacutely reducing LGI1 expression with shRNA. RESULTS: Injection of shRNA-LGI1 in the hippocampus increased dentate granule cell excitability and low-frequency facilitation of mossy fibers to CA3 pyramidal cell neurotransmission. Application of the Kv1 family blocker, α-dendrotoxin, occluded this effect, implicating the involvement of Kv1.1. This subacute reduction of LGI1 was also sufficient to increase neuronal network activity in neuronal primary culture. SIGNIFICANCE: These results indicate that a subacute reduction in LGI1 potentiates neuronal excitability and short-term synaptic plasticity, and increases neuronal network excitability, opening new avenues for the treatment of limbic encephalitis and temporal lobe epilepsies.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Neurônios/fisiologia , Convulsões/etiologia , Animais , Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Canal de Potássio Kv1.1/metabolismo , Canal de Potássio Kv1.1/fisiologia , Camundongos , Camundongos Knockout , Comunicação Parácrina , RNA Interferente Pequeno , Convulsões/fisiopatologia , Sinapses/metabolismo , Sinapses/fisiologia
3.
Brain ; 142(11): 3398-3410, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31591639

RESUMO

Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here, purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome, and glycine receptor autoantibodies, were observed to disrupt profoundly glycinergic neurotransmission. In whole-cell patch clamp recordings from cultured rat spinal motor neurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-d-aspartate (NMDA) receptors, affect whole cell currents only after several hours incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalization of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 min of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors.


Assuntos
Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/imunologia , Receptores de Glicina/antagonistas & inibidores , Transmissão Sináptica/imunologia , Idoso , Animais , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Imunoglobulina G/genética , Masculino , Pessoa de Meia-Idade , Neurônios Motores/efeitos dos fármacos , Técnicas de Patch-Clamp , Gravidez , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Rigidez Muscular Espasmódica/imunologia , Sinapses/efeitos dos fármacos
4.
J Neurosci ; 39(16): 3159-3169, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30755487

RESUMO

Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon optimized for human expression and mutated to accelerate the recovery of the channels from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a nonintegrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled preclinical trial, the EKC lentivector robustly reduced seizure frequency in a male rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. When packaged into an adeno-associated viral vector (AAV2/9), the EKC gene was also effective at suppressing seizures in a male rat model of temporal lobe epilepsy. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as being ready for clinical translation in the treatment of refractory focal epilepsy.SIGNIFICANCE STATEMENT Pharmacoresistant epilepsy affects up to 0.3% of the population. Although epilepsy surgery can be effective, it is limited by risks to normal brain function. We have developed a gene therapy that builds on a mechanistic understanding of altered neuronal and circuit excitability in cortical epilepsy. The potassium channel gene KCNA1 was mutated to bypass post-transcriptional editing and was packaged in a nonintegrating lentivector to reduce the risk of insertional mutagenesis. A randomized, blinded preclinical study demonstrated therapeutic effectiveness in a rodent model of focal neocortical epilepsy. Adeno-associated viral delivery of the channel to both hippocampi was also effective in a model of temporal lobe epilepsy. These results support clinical translation to address a major unmet need.


Assuntos
Encéfalo/metabolismo , Epilepsia/terapia , Terapia Genética , Canal de Potássio Kv1.1/genética , Convulsões/terapia , Animais , Modelos Animais de Doenças , Epilepsia/genética , Vetores Genéticos , Canal de Potássio Kv1.1/metabolismo , Masculino , Ratos , Convulsões/genética
5.
Dis Model Mech ; 11(12)2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30467223

RESUMO

Focal neocortical epilepsy is a common form of epilepsy and there is a need to develop animal models that allow the evaluation of novel therapeutic strategies to treat this type of epilepsy. Tetanus toxin (TeNT) injection into the rat visual cortex induces focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days. Seizure duration was bimodal, with both short (approximately 30 s) and long-lasting (>100 s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonic-clonic seizures. Seizures were more common during the sleep phase of a light-dark cycle. Seizure occurrence was not random, and tended to cluster with significantly higher probability of recurrence within 24 h of a previous seizure. Across animals, the number of seizures in the first week could be used to predict the number of seizures in the following 3 weeks. The TeNT model of occipital cortical epilepsy is a model of acquired focal neocortical epilepsy that is well-suited for preclinical evaluation of novel anti-epileptic strategies. We provide here a detailed analysis of the epilepsy phenotypes, seizure activity, electrographic features and the semiology. In addition, we provide a predictive framework that can be used to reduce variation and consequently animal use in preclinical studies of potential treatments.


Assuntos
Progressão da Doença , Epilepsia/patologia , Lobo Occipital/patologia , Periodicidade , Convulsões/patologia , Animais , Comportamento Animal , Análise por Conglomerados , Modelos Animais de Doenças , Eletrocorticografia , Injeções , Luz , Masculino , Estimulação Luminosa , Ratos Sprague-Dawley , Toxina Tetânica/administração & dosagem , Córtex Visual/patologia
6.
Am J Hum Genet ; 95(5): 590-601, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25439726

RESUMO

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Exoma/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Fenótipo , Adulto , Sequência de Bases , Doença de Charcot-Marie-Tooth/patologia , Mapeamento Cromossômico , Feminino , Haplótipos/genética , Humanos , Dados de Sequência Molecular , Linhagem , Mapeamento de Interação de Proteínas , Análise de Sequência de DNA , Nervo Sural/patologia
7.
Prog Brain Res ; 214: 229-62, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25410361

RESUMO

Currently, there are about 20 antiepileptic drugs on market. Still, seizures in about 30% of patients with epilepsy are not adequately controlled, or the drugs cause quality-of-life-compromising adverse events. Importantly, there are no treatments to combat epileptogenesis, a process that leads to the development of epilepsy and its progression. To fill the gaps in the treatment of epilepsy, there is an urgent need for identification of novel treatment targets. Data emerging over the recent years have shown that different components of the extracellular matrix (ECM) contribute to many components of tissue reorganization during epileptogenesis and the ECM is also a major regulator of synaptic excitability. Here, we review the role of urokinase-type plasminogen activator receptor interactome, matrix metalloproteinases, tenascin-R, and LGI1 in epileptogenesis and ictogenesis. Moreover, the role of the ECM in epilepsy-related comorbidities is reviewed. As there is active development of new imaging methods, we also summarize the data available on imaging of the ECM in epilepsy.


Assuntos
Epilepsia/patologia , Matriz Extracelular/fisiologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Matriz Extracelular/efeitos dos fármacos , Humanos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos
8.
Epilepsy Res ; 107(3): 311-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24206907

RESUMO

Mutations in LGI1 are found in 50% of families with autosomal dominant epilepsy with auditory features (ADEAF). In ADEAF, family members have predominantly lateral temporal lobe seizures but mesial temporal lobe semiology may also occur. We report here three families with novel LGI1 mutations (p.Ile82Thr, p.Glu225*, c.432-2_436del). Seven affected individuals reported an auditory aura and one a visual aura. A 10-year old boy described a cephalic aura followed by an unpleasant taste and oral automatisms without auditory, visual or psychic features.


Assuntos
Epilepsia Reflexa/diagnóstico , Epilepsia Reflexa/genética , Mutação/genética , Proteínas/genética , Convulsões/diagnóstico , Convulsões/genética , Estimulação Acústica/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Estimulação Luminosa/efeitos adversos , Adulto Jovem
9.
Neuron ; 75(4): 633-47, 2012 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-22920255

RESUMO

The radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.


Assuntos
Regeneração Nervosa/fisiologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Células de Schwann/metabolismo , Neuropatia Ciática/patologia , Adenoviridae/genética , Análise de Variância , Animais , Benzofuranos , Movimento Celular/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Vetores Genéticos/fisiologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/ultraestrutura , Camundongos , Camundongos Transgênicos , Técnicas Analíticas Microfluídicas , Microscopia Eletrônica de Transmissão , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Neurônios Motores/ultraestrutura , Bainha de Mielina/patologia , Bainha de Mielina/ultraestrutura , Proteínas Proto-Oncogênicas c-jun/genética , Células de Schwann/patologia , Células de Schwann/ultraestrutura , Neuropatia Ciática/metabolismo , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/terapia , Medula Espinal/patologia
10.
Neurobiol Aging ; 32(3): 557.e11-3, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21220178

RESUMO

Mutations in OPTN gene encoding optineurin have recently been identified at the homozygote and heterozygote state in Japanese families with slowly progressive amyotrophic lateral sclerosis (ALS). OPTN had previously been involved in adult primary open angle glaucoma (POAG). We sequenced the coding exons of OPTN in 126 French patients with familial ALS (FALS). We identified, at the heterozygote state, the nonsense c.382_383insAG variant (also called 691_692insAG), alternatively reported as a causative mutation for primary open angle glaucoma (POAG) or a rare polymorphism and the new p.Arg96Leu variant in a family with dominant ALS. Western blot experiments on the patients' lymphoblasts showed that the former variant led to a loss of function and the latter did not cause protein accumulation. Our results do not confirm the contribution of OPTN in ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Saúde da Família , Testes Genéticos/métodos , Mutação/genética , Fator de Transcrição TFIIIA/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Proteínas de Ciclo Celular , Biologia Computacional , Éxons/genética , Feminino , França/epidemiologia , Genótipo , Glaucoma de Ângulo Aberto/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras , Fator de Transcrição TFIIIA/metabolismo
11.
Cell Tissue Res ; 343(3): 521-36, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21191615

RESUMO

The enzyme tissue non-specific alkaline phosphatase (TNAP) belongs to the ectophosphatase family. It is present in large amounts in bone in which it plays a role in mineralization but little is known about its function in other tissues. Arguments are accumulating for its involvement in the brain, in particular in view of the neurological symptoms accompanying human TNAP deficiencies. We have previously shown, by histochemistry, alkaline phosphatase (AP) activity in monkey brain vessels and parenchyma in which AP exhibits specific patterns. Here, we clearly attribute this activity to TNAP expression rather than to other APs in primates (human and marmoset) and in rodents (rat and mouse). We have not found any brain-specific transcripts but our data demonstrate that neuronal and endothelial cells exclusively express the bone TNAP transcript in all species tested, except in mouse neurons in which liver TNAP transcripts have also been detected. Moreover, we highlight the developmental regulation of TNAP expression; this also acts during neuronal differentiation. Our study should help to characterize the regulation of the expression of this ectophosphatase in various cell types of the central nervous system.


Assuntos
Fosfatase Alcalina/metabolismo , Osso e Ossos/enzimologia , Encéfalo/enzimologia , Isoenzimas/metabolismo , Fígado/enzimologia , Fosfatase Alcalina/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Vasos Sanguíneos/enzimologia , Linhagem Celular , Embrião de Mamíferos/anatomia & histologia , Embrião de Mamíferos/enzimologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dados de Sequência Molecular , Primatas , Estrutura Terciária de Proteína , Ratos , Alinhamento de Sequência , Distribuição Tecidual
12.
Brain ; 133(9): 2749-62, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20659958

RESUMO

Mutations of the LGI1 (leucine-rich, glioma-inactivated 1) gene underlie autosomal dominant lateral temporal lobe epilepsy, a focal idiopathic inherited epilepsy syndrome. The LGI1 gene encodes a protein secreted by neurons, one of the only non-ion channel genes implicated in idiopathic familial epilepsy. While mutations probably result in a loss of function, the role of LGI1 in the pathophysiology of epilepsy remains unclear. Here we generated a germline knockout mouse for LGI1 and examined spontaneous seizure characteristics, changes in threshold for induced seizures and hippocampal pathology. Frequent spontaneous seizures emerged in homozygous LGI1(-/-) mice during the second postnatal week. Properties of these spontaneous events were examined in a simultaneous video and intracranial electroencephalographic recording. Their mean duration was 120 +/- 12 s, and behavioural correlates consisted of an initial immobility, automatisms, sometimes followed by wild running and tonic and/or clonic movements. Electroencephalographic monitoring indicated that seizures originated earlier in the hippocampus than in the cortex. LGI1(-/-) mice did not survive beyond postnatal day 20, probably due to seizures and failure to feed. While no major developmental abnormalities were observed, after recurrent seizures we detected neuronal loss, mossy fibre sprouting, astrocyte reactivity and granule cell dispersion in the hippocampus of LGI1(-/-) mice. In contrast, heterozygous LGI1(+/-) littermates displayed no spontaneous behavioural epileptic seizures, but auditory stimuli induced seizures at a lower threshold, reflecting the human pathology of sound-triggered seizures in some patients. We conclude that LGI1(+/-) and LGI1(-/-) mice may provide useful models for lateral temporal lobe epilepsy, and more generally idiopathic focal epilepsy.


Assuntos
Epilepsia Reflexa/genética , Proteínas/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Encéfalo/fisiopatologia , Lesões Encefálicas/etiologia , Proteínas de Transporte/metabolismo , Proteínas de Transporte de Cátions , Modelos Animais de Doenças , Eletroencefalografia/métodos , Epilepsia Reflexa/complicações , Epilepsia Reflexa/etiologia , Epilepsia Reflexa/patologia , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravação em Vídeo/métodos
13.
Epilepsy Res ; 85(1): 118-22, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19268539

RESUMO

Mutations in LGI1 have been reported in several families with autosomal dominant lateral temporal epilepsy. In a family in which three patients also experienced migraine-like episodes we found a novel three base-pair deletion (c.377_379delACA), resulting in the deletion of an asparagine residue in the second leucine-rich repeat. Functional studies showed that the mutated protein was not secreted when transfected in COS cells, consistent with a causative role in the disease.


Assuntos
Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/genética , Saúde da Família , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/genética , Proteínas/genética , Deleção de Sequência/genética , Adolescente , Adulto , Idoso , Animais , Asparagina/genética , Células COS , Chlorocebus aethiops , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Transfecção/métodos
14.
Epilepsy Res ; 76(1): 41-8, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17681454

RESUMO

Mutations in the LGI1 (leucine-rich, glioma inactivated 1) gene are found in less than a half of the families with autosomal dominant lateral temporal epilepsy (ADLTE), suggesting that ADLTE is a genetically heterogeneous disorder. Recently, it was shown that LGI1 is released by neurons and becomes part of a protein complex at the neuronal postsynaptic density where it is implicated in the regulation of glutamate-AMPA neurotransmission. Within this complex, LGI1 binds selectively to a neuronal specific membrane protein, ADAM22 (a disintegrin and metalloprotease). Since ADAM22 serves as a neuronal receptor for LGI1, the ADAM22 gene was considered a good candidate gene for ADLTE. We have therefore sequenced all coding exons and exon-intron flanking sites in the ADAM22 gene in the probands of 18 ADLTE families negative for LGI1 mutations. Although, we identified several synonymous and non-synonymous polymorphisms, we failed to identify disease-causing mutations, indicating that ADAM22 gene is probably not a major gene for this epilepsy syndrome.


Assuntos
Proteínas ADAM/genética , Epilepsia do Lobo Temporal/genética , Saúde da Família , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA/métodos , Feminino , Testes Genéticos/métodos , Humanos , Masculino
15.
Arch Neurol ; 64(2): 217-22, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17296837

RESUMO

BACKGROUND: Mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been implicated in autosomal dominant lateral temporal epilepsy. OBJECTIVE: To describe the clinical and genetic findings in 2 families with autosomal dominant lateral temporal epilepsy and the functional consequences of 2 novel mutations in LGI1. DESIGN: Clinical, genetic, and functional investigations. SETTING: University hospital. Patients Two French families with autosomal dominant lateral temporal epilepsy. Main Outcome Measure Mutation analysis. RESULTS: Two novel disease-linked mutations, p.Leu232Pro and c.431 + 1G>A, were identified in LGI1. We demonstrated that the c.431 + 1G>A mutation causes the deletion of exons 3 and 4 of the LGI1 transcript and showed that the p.Leu232Pro mutation dramatically decreases secretion of the mutant protein by mammalian cells. CONCLUSION: Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function.


Assuntos
Epilepsia/genética , Mutação/genética , Proteínas/genética , Adulto , Western Blotting/métodos , Análise Mutacional de DNA , Éxons , Saúde da Família , Feminino , Ligação Genética/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucina/genética , Masculino , Pessoa de Meia-Idade , Prolina/genética , Proteínas/metabolismo , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Índice de Gravidade de Doença
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...