Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology

GABA-A 受体亚基缺失对 Angelman 综合征病理生理学的贡献

• 批准号: 10391880
• 负责人: Eric S Levine
• 金额: $ 45.1万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391880
• 关键词: Affect; Alleles; Angelman Syndrome; Animal Model; Animals; Antisense Oligonucleotides; Behavioral; Brain; Cell Line; Chromosome Deletion; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Cognitive deficits; Data; Development; Electrophysiology (science); Epilepsy; Functional disorder; GABA Receptor; GABA-A Receptor; Gene Cluster; Gene Expression; Gene Mutation; Genes; Genetic; Goals; Human; Incidence; Individual; Inhibitory Synapse; Intellectual functioning disability; Knock-out; Light; Measures; Modeling; Molecular; Monitor; Motor; Motor Ataxias; Mutation; Neurodevelopmental Disorder; Neurons; Patients; Phenotype; Physiological; Population; Predisposition; Prevalence; Property; Resources; Rodent; Role; Seizures; Severities; Signal Transduction; Speech; Synapses; Synaptic Transmission; Syndrome; Testing; UBE3A gene; autism spectrum disorder; developmental disease; experimental study; genome editing; imprint; induced pluripotent stem cell; innovation; interest; knock-down; loss of function mutation; motor deficit; multi-electrode arrays; neurogenetics; neuronal excitability; new therapeutic target; novel; novel therapeutics; patch clamp; patient subsets; receptor; synaptic inhibition; therapeutic development; tool; transmission process; ubiquitin-protein ligase

PROJECT SUMMARY Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A, although other genes in the region are also deleted. AS can also result from loss of function mutations of UBE3A, which spares the other genes located in the region. UBE3A mutation AS patients typically have a milder phenotype, especially with regard to epilepsy and seizures. This suggests that the loss of other genes in the region, in addition to UBE3A, likely contribute to the severe epilepsy phenotype in deletion AS patients. In particular, a cluster of genes encoding three GABAA receptor subunits is located within the region typically deleted in AS. Reduced expression of these subunits has been implicated in several human neurodevelopmental disorders such as Angelman syndrome, certain syndromic forms of epilepsy, and autism. We hypothesize that hemizygous loss of GABRB3, GABRA5, and/or GABRG3, in conjunction with loss of UBE3A expression, causes neuronal hyperexcitability and enhanced seizure susceptibility in human AS individuals. We will test this hypothesis by comparing the physiological phenotype of AS neurons derived from mutation and deletion AS patients. We will use antisense oligonucleotide approaches to determine if knocking down expression of these GABA receptor subunits in a UBE3A deficient line will confer the increased excitability seen in neurons derived from AS deletion patients. These studies will shed light on the cellular mechanisms responsible for seizures in AS and identify targets for development of novel therapeutics.

项目摘要 染色体15 q11-q13缺失的个体患有安格尔曼综合征（AS），这是一种神经遗传性疾病。 以智力残疾、运动性共济失调、言语缺失和癫痫发作为特征的发育障碍。的 负责AS的特定基因编码遍在蛋白连接酶UBE 3A，尽管AS中的其他基因 区域也被删除。AS也可能是由UBE 3A的功能缺失突变引起的，这使得另一个基因的功能缺失突变得以保留。 基因位于该地区。UBE 3A突变AS患者通常具有较轻的表型，尤其是 关于癫痫和癫痫发作。这表明，除了UBE 3A之外，该区域其他基因的丢失， 可能导致缺失型AS患者的严重癫痫表型。特别是一组基因 编码三个GABAA受体亚单位的基因位于AS中通常缺失的区域内。表达降低 这些亚基的存在与几种人类神经发育障碍有关， 综合征、某些癫痫综合征和自闭症。我们假设半合子GABRB 3缺失， GABRA 5和/或GABRG 3与UBE 3A表达的丧失结合，引起神经元过度兴奋， 增强人类AS个体的癫痫发作易感性。我们将通过比较 突变型和缺失型AS患者的AS神经元生理表型。我们将使用反义 寡核苷酸方法来确定是否敲低这些GABA受体亚单位在一个细胞中的表达。 UBE 3A缺陷系将赋予在源自AS缺失患者的神经元中观察到的增加的兴奋性。 这些研究将阐明AS癫痫发作的细胞机制，并确定治疗的靶点。 开发新的治疗方法。