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：
9265144
负责人：
EDWARD C COOPER
金额：
$ 36.72万
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265144
关键词：
Action Potentials Acute Adult Affect Anatomy 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 Pharmacology 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 comparative efficacy design early onset effective therapy epileptic encephalopathies experimental study genetic pedigree human tissue in vivo multidisciplinary mutant neocortical novel patch clamp postnatal preclinical efficacy preclinical safety public health relevance 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 突变会导致良性家族性新生儿癫痫发作 (BFNS)，这是一种显性遗传的、高渗透性的早发性癫痫综合征。 BFNS 在新生儿期引起频繁的癫痫发作，但癫痫发作缓解后，受影响的个体发育正常。然而，现在令人信服的证据表明，KCNQ2 突变的一个子集与持续性和致残性中枢神经系统和神经肌肉疾病有关。 KCNQ2谱系表现出疼痛性肌颤动（无癫痫发作）、新生儿癫痫发作后肌颤动、新生儿期后癫痫以及伴有明显智力障碍的癫痫。最重要的是，最近的一项欧洲-澳大利亚合作研究描述了 10% (8/80) 的严重、散发、早发性癫痫性脑病 (EEE) 病例中存在新发 KCNQ2 突变。正如本更新申请中所披露的，我们的实验室已确定来自北美的另外 6 名 EEE 患者携带新的 KCNQ2 突变。尽管遗传背景和表观遗传学等因素可能影响这些表型，但我们的分析表明，EEE 患者中的新生 KCNQ2 突变可能充当有效的显性失活，抑制活性高达 94%（16 倍），而已知的 BFNS 突变已知通常会使活性降低 20-50%（2 倍或更少）。在这里，我们建议定义包含 KCNQ2 和 KCNQ3 的通道到达海马结构以及体感和运动新皮质神经元轴突膜的发育时间过程，并在正常啮齿动物、KCNQ2 突变小鼠和人体组织中进行测定。在解剖学研究的同时，我们还将通过体外分析、膜片钳记录和转基因动物模型，在亚细胞、细胞和行为水平上分析海马和新皮质轴突KCNQ通道的功能。最后，我们将分析和比较两种在效力、最大功效和亚基特异性方面不同的 KCNQ 开启剂药物在体外激活通道和终止体内癫痫发作的功效。