KCNQ2/3 channels in neonatal-onset epilepsy and encephalopathy

KCNQ2/3 通道在新生儿癫痫和脑病中的作用

基本信息

批准号：
8505736
负责人：
EDWARD C COOPER
金额：
$ 34.23万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505736
关键词：
Action Potentials Acute Adult Affect Animal Model Antiepileptic Agents Behavioral Benign Biological Assay Biophysics Birth Brain Cell Line Cells Central Nervous System Diseases Clinical Custom Development Developmental Delay Disorders Disease Dominant-Negative Mutation Early treatment Electrophysiology (science)Encephalopathies Epigenetic Process Epilepsy Esthesia Exhibits FDA approved Genetic Genetic Variation Goals Health Hippocampal Formation Hippocampus (Brain)Human In Vitro Individual Inherited Injury Intellectual functioning disability Ion Channel Learning Life Link Membrane Molecular Biology Motor Movement Mus Mutant Strains Mice Mutation Myokymia Neocortex Neonatal Neuromuscular Diseases Neurons North America Pain Patients Pharmaceutical Preparations Phenotype Predisposition Property Proteins Ranvier&apos s Nodes Rodent Seizures Severities Signal Transduction Site Slice Specificity Status Epilepticus Symptoms Syndrome Testing Thinking Time Toxic effect Transfection Transgenic Animals Transgenic Organisms Variant Voltage-Gated Potassium Channel Work base comparative efficacy design early onset effective therapy genetic pedigree human tissue in vivo multidisciplinary mutant neocortical novel patch clamp postnatal preclinical efficacy preclinical safety public health relevance research study safety testing somatosensory

项目摘要

DESCRIPTION (provided by applicant): Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal seizures (BFNS), a dominantly-inherited, highly penetrant early-onset epilepsy syndrome. BFNS causes frequent seizures during the neonatal period, but after seizures remit, affected individuals develop normally. However, compelling evidence now implicates a subset of KCNQ2 mutations in persistent and disabling CNS and neuromuscular diseases. KCNQ2 pedigrees exhibit painful myokymia (without seizures), myokymia after neonatal seizures, epilepsy after the neonatal period, and epilepsy with significant intellectual disability. Most importantly, a recent Euro-Australian collaborative study describes de novo KCNQ2 mutations in 10% of cases (8/80) of severe, sporadic, early- onset epileptic encephalopathy (EEE). As disclosed in this renewal application, our lab has ascertained 6 additional individuals from North America with EEE bearing novel KCNQ2 mutations. Although factors such as genetic background and epigenetics may influence these phenotypes, our analysis suggests mechanisms whereby the de novo KCNQ2 mutations in EEE patients may act as potent dominant-negatives, suppressing activity up to 94% (16-fold), whereas known BFNS mutations are known to generally reduce activity by 20-50% (2-fold or less). Here, we propose to define the developmental time course for the arrival of KCNQ2 and KCNQ3-containing channels at the axonal membrane of neurons in the hippocampal formation and the somatosensory and motor neocortex, assayed in normal rodents, KCNQ2 mutant mice, and human tissue. In parallel with anatomical study, we will also analyze the function of hippocampal and neocortical axonal KCNQ channels at the subcellular, cellular, and behavioral level through in vitro analysis, patch clamp recording, and transgenic animal models. Finally, we will analyze and compare the efficacy two KCNQ opener drugs which differ in potency, maximal efficacy and subunit specificity, to activate channels in vitro and terminate seizures in vivo.

描述（由申请人提供）：KCNQ2或KCNQ3中的突变会导致良性家族性新生儿癫痫发作（BFNS），这是一种主要具有高度渗透性的早期发作的癫痫综合征。 BFN在新生儿期间引起频繁的癫痫发作，但在癫痫发作后，受影响的个体正常发展。然而，令人信服的证据现在暗示了持续性和禁用CNS和神经肌肉疾病的KCNQ2突变的子集。 KCNQ2血统表现出疼痛的肌动物症（无癫痫发作），新生儿癫痫发作后的肌科，新生儿时期的癫痫病以及具有重大智力障碍的癫痫病。最重要的是，最近的一项欧洲 - 澳大利亚合作研究描述了从10％（8/80）的严重，零星，早期发作早期癫痫性脑病（EEE）病例（8/80）中的Novo KCNQ2突变。正如在此续签应用中所披露的那样，我们的实验室已经确定了来自北美的6个人，并具有带有新型KCNQ2突变的EEE。尽管诸如遗传背景和表观遗传学之类的因素可能会影响这些表型，但我们的分析提出了机制，即EEE患者的NOVO KCNQ2突变可能充当有效的显性阴性，从而抑制了高达94％（16倍）的活性，而知道已知的BFN突变通常会减少20-50％（2倍）（2倍）。在这里，我们建议定义KCNQ2和KCNQ3通道在海马形成中神经元的轴突膜上的到达的发育时间过程，并在正常啮齿动物中测定了kcnq2突变小鼠和人类组织，并测定了在正常啮齿动物中测定的体感和运动新皮层。与解剖学研究同时，我们还将通过体外分析，斑块记录和转基因动物模型分析亚细胞，细胞和行为水平在亚细胞，细胞和行为水平上海马和新皮层KCNQ通道的功能。最后，我们将分析和比较两种KCNQ开瓶药物的功效，这些药物的效力，最大疗效和亚基特异性不同，以在体外激活通道和终止体内癫痫发作。