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

基本信息

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
项目类别：
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

项目摘要

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，一生中将影响26名美国人中的1个。有一系列严重性，发育和癫痫性脑病（DEES）是最重要的严重且在医学上具有挑战性。蠕虫是一个以婴儿为特征的异源性疾病群对可用治疗，脑电图（EEG）异常的反应不佳的发作癫痫发作，发育延迟/智力残疾和死亡率升高。蠕变主要是由于单基因引起的在受影响的孩子中从头出现的变体。尽管每个基于基因的病因很少钢铁的发病率估计为2,000名活产，代表了巨大的公共卫生负担。贫穷的对可用治疗的反应是dees的定义特征，代表了对有效的疗法。尽管多种遗传病因表明最终公共途径的破坏是这些表型的基础。识别修饰符基因这种广泛影响癫痫的渗透和表现力可能揭示了这些共同的途径。我们的先前的工作表明，修饰基因通常调节多个单基因dees的功能，而这些基因相同的基因也被认为是具有复杂遗传基础的常见癫痫中的风险基因。在当前的研究，我们建议使用带有新开发的小鼠模型来识别修饰剂基因人DEE变体KCNB1-P.G379R被确定为与之相关的致病变体发育延迟/智力残疾，自闭症谱系障碍的特征，异常背景脑电图和多种癫痫发作类型对可用治疗的反应不佳。我们最近开发了一个KCNB1G379R小鼠模型，该模型概括了临床表型的核心方面，包括自发复发性癫痫发作，背景性脑电图异常和神经行为改变。表型严重程度取决于应变背景，这表明修饰符基因的贡献。基于这些观察结果，我们假设KCNB1G379R DEE模型中的表型严重程度受遗传的影响修饰符。我们将在三个Subaims中解决我们的中心假设。首先，我们将确定癫痫发作和脑电图使用BXD重组亲菌株在多种遗传面板上KCNB1G379R小鼠中的表型严重程度。其次，我们将在C57BL/6J上的KCNB1G379R和WT小鼠之间的基因表达差异分类和[C57BL/6J] F1菌株。第三，我们将通过穿孔QTL整合Subaims 1A和1B的信息映射和候选基因分析以识别影响的修饰基因座和推定的糖果基因癫痫的严重程度。促进我们对KCNB1-的癫痫基因网络架构的理解 - 相关的DEE将促进有针对性的治疗干预措施的发展，并有可能受益于大量的DEE和其他癫痫病。