Genetic Mapping of Modifier Loci in a Mouse Model KCNB1 Encephalopathy

KCNB1 脑病小鼠模型修饰位点的遗传图谱

• 批准号: 10753301
• 负责人: Jennifer A Kearney
• 金额: $ 24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753301
• 关键词: Address; Affect; American; Behavioral; Brain region; Candidate Disease Gene; Case Study; Catalogs; Cessation of life; Characteristics; Child; Chromosome Mapping; Clinical; Code; Complex; Copy Number Polymorphism; DNA; Data; Data Set; Development; Developmental Delay Disorders; Disease; Dominant-Negative Mutation; Electroencephalography; Encephalopathies; Epilepsy; Etiology; Exhibits; Family; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Health; Heritability; Hippocampus; Human; Hybrids; Inbred Mouse; Inbred Strains Mice; Inbreeding; Incidence; Individual; Infant; Intellectual functioning disability; Knowledge; Live Birth; Longevity; Maps; Medical; Modeling; Mus; Neurodevelopmental Disorder; Neurosciences; Pathogenicity; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Public Health; Quantitative Trait Loci; Recombinant Inbred Strain; Recombinants; Recurrence; Refractory; Reporting; Risk; Seizures; Severities; Single Nucleotide Polymorphism; Societies; Testing; Therapeutic Intervention; Transcript; Validation; Variant; Voltage-Gated Potassium Channel; Work; autism spectrum disorder; clinical phenotype; effective therapy; epileptic encephalopathies; gene function; gene network; genetic variant; human model; improved; improved outcome; mortality risk; mouse model; nervous system disorder; network architecture; neurobehavior; novel therapeutic intervention; patient population; resistant strain; response; risk variant; targeted treatment; trait; transcriptome; transcriptome sequencing

PROJECT SUMMARY Epilepsy is a common neurological disorder that will affect 1 in 26 Americans during their lifetime. There is a range of severity, with developmental and epileptic encephalopathies (DEEs) being among the most severe and medically challenging. DEEs are a heterogenous group of disorders characterized by infant- onset seizures that respond poorly to available treatments, electroencephalographic (EEG) abnormalities, developmental delay/intellectual disability, and elevated mortality risk. DEEs are primarily due to monogenic variants that arise de novo in the affected child. Although each gene-based etiology is rare, collectively the incidence of DEEs is estimated at 1 in 2,000 live births, representing a significant public health burden. Poor response to available treatments is a defining feature of DEEs, representing a significant unmet need for effective therapies. DEEs share overlapping clinical characteristics despite multiple genetic etiologies, suggesting that disruption of final common pathways underlies these phenotypes. Identifying modifier genes that broadly influence epilepsy penetrance and expressivity may reveal these shared pathways. Our previous work showed that modifier genes often modulate function of multiple monogenic DEEs, and these same genes are also implicated as risk genes in common epilepsies with complex genetic basis. In the current study, we propose to identify modifier genes using a newly developed mouse model carrying the human DEE variant KCNB1-p.G379R that was identified as a pathogenic variant associated with developmental delay/intellectual disability, features of autism spectrum disorder, abnormalities in background EEG, and multiple seizure types that responded poorly to available treatments. We recently developed a Kcnb1G379R mouse model that recapitulates core aspects of the clinical phenotype, including spontaneous recurrent seizures, abnormalities in background EEG, and altered neurobehavior. Phenotype severity is dependent on strain background, suggesting a contribution of modifier genes. Based on these observations, we hypothesize that phenotype severity in the Kcnb1G379R DEE model is influenced by genetic modifiers. We will address our central hypothesis in three subaims. First, we will ascertain seizure and EEG phenotype severity in Kcnb1G379R mice on a diverse genetic panel using BxD recombinant inbred strains. Second, we will catalog differences in gene expression between Kcnb1G379R and WT mice on the C57BL/6J and [C57BL/6J]F1 strains. Third, we will integrate information from subaims 1A and 1B by perforning QTL mapping and candidate gene analysis to identify modifier loci and putative candiate genes that influence epilepsy severity. Advancing our understanding of the epilepsy gene network architecture for KCNB1- associated DEE will promote development of targeted therapeutic interventions and has the potential to benefit a broad population of individuals with DEE and other epilepsies.

项目摘要 癫痫是一种常见的神经系统疾病，每26个美国人中就有1个会在一生中受到影响。有 一系列的严重程度，其中发育性和癫痫性脑病（DEE）是最常见的 严重且具有医学挑战性。DEE是一组异质性疾病，其特征是婴儿- 对现有治疗反应不佳的发作性癫痫，脑电图（EEG）异常， 发育迟缓/智力残疾和死亡风险升高。DEE主要是由于单基因 在受影响的儿童中重新出现的变异。虽然每一个基因为基础的病因是罕见的，总的来说， DEE的发病率估计为每2，000例活产中有1例，这是一个重大的公共卫生负担。贫困 对现有治疗的反应是DEE的一个定义特征，代表了对以下方面的重大未满足需求： 有效的治疗。尽管有多种遗传病因，但DEE具有重叠的临床特征， 这表明最终共同途径的破坏是这些表型的基础。识别修饰基因 广泛影响癫痫发作的行为和表达可能揭示了这些共同的途径。我们 以前的工作表明，修饰基因经常调节多个单基因DEE的功能，这些单基因DEE 这些基因也是常见癫痫的危险基因，遗传基础复杂。在 目前的研究，我们建议使用新开发的小鼠模型，携带 人DEE变体KCNB1-p.G379R，其被鉴定为与 发育迟缓/智力残疾，自闭症谱系障碍的特征， 背景EEG和多种癫痫发作类型，对现有治疗反应不佳。我们最近 开发了Kcnb1G379R小鼠模型，该模型概括了临床表型的核心方面，包括 自发性复发性癫痫发作、背景EEG异常和神经行为改变。表型 严重程度取决于菌株背景，表明修饰基因的贡献。基于这些 通过观察，我们假设Kcnb1G379R DEE模型中的表型严重程度受遗传因素的影响， 修饰语我们将在三个子目标中阐述我们的中心假设。首先我们要确定癫痫发作和脑电图 使用BxD重组近交系在不同遗传面板上的Kcnb1G379R小鼠中的表型严重性。 其次，我们将对C57 BL/6J上Kcnb1G379R和WT小鼠之间的基因表达差异进行分类， 和[C57BL/6J] F1菌株。第三，通过QTL定位，整合子目标1A和1B的信息 定位和候选基因分析，以鉴定修饰基因座和推定的候选基因， 癫痫严重程度。推进我们对KCNB1癫痫基因网络结构的理解- 相关的DEE将促进靶向治疗干预的发展，并有可能 使广泛的DEE和其他癫痫患者受益。