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Genetic Modifiers of Childhood Epilepsy

儿童癫痫的基因修饰

基本信息

批准号：
9980137
负责人：
Jennifer A Kearney
金额：
$ 51.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980137
关键词：
129 Mouse Address Affect Age Age-Months Alleles American Animals Behavioral Brain Buffers Candidate Disease Gene Cell Nucleus Cells Chromosome 7 Chromosome 8 Chromosomes Clinical Code Cognitive Complex Congenic Strain DNA Data Data Set Development Developmental Delay Disorders Disease Epilepsy Etiology Evaluation Exhibits Failure Febrile Convulsions Functional disorder Gene Expression Gene-Modified Genes Genetic Genetic Predisposition to Disease Genetic Transcription Goals Hippocampus (Brain)Human Individual Infant Inherited Intellectual functioning disability Interneurons Ion Channel Longevity Maps Medicine Mus Mutation Neurologic Neurons Pathogenicity Pathway interactions Patients Phase Phenotype Population Proteins QTL Genes Quantitative Trait Loci Refractory Reporting Resistance Resolution Risk Seizures Severities Severity of illness Small Nuclear RNA Sodium Sodium Channel Surveys Synapses Syndrome Transcriptional Regulation Variant base cell type childhood epilepsy density differential expression dravet syndrome epileptic encephalopathies genetic pedigree improved in vivo insight loss of function loss of function mutation mortality risk nervous system disorder neurotransmission novel therapeutic intervention novel therapeutics premature preservation promoter response risk variant single-cell RNA sequencing sudden unexpected death in epilepsy therapeutic target trait transcriptome sequencing voltage

项目摘要

Epilepsy is a common neurological that will affect 1 in 26 Americans during their lifetime. Mutations in SCN1A, encoding the neuronal voltage-gated sodium channel Nav1.1, are the most common genetic cause of epilepsy. Over 1600 SCN1A mutations have been reported in individuals with epilepsy of varying severity, ranging from mild febrile seizures to Dravet syndrome, a severe infant-onset epileptic encephalopathy caused by heterozygous loss-of-function mutations. Dravet syndrome is characterized by a variety of seizure types, developmental delay and elevated mortality risk. A common feature of monogenic epilepsies is variable expressivity in individuals carrying the same mutation, suggesting that clinical severity is influenced by genetic modifiers. Mice with heterozygous deletion of Scn1a (Scn1a+/-) recapitulate core features of Dravet syndrome phenotypes, including spontaneous seizures and increased mortality risk. Loss of Scn1a results in reduced sodium current in hippocampal GABAergic interneurons, resulting in failure of inhibition and excitatory/inhibitory imbalance in the brain. Phenotype severity in Scn1a+/- mice is strongly dependent on strain background. Scn1a+/- mice on the resistant 129 strain (129.Scn1a+/-) have no overt phenotype and live a normal lifespan. In contrast, Scn1a+/- mice on a [129xB6]F1 strain (F1.Scn1a+/-) exhibit spontaneous seizures and premature lethality, with 50% dying by 1 month of age. Strain-dependent differences are also evident at the level of neuron subtypes. GABAergic interneurons isolated from the susceptible F1.Scn1a+/- mice exhibit decreased sodium current density compared to wildtype littermates, while sodium current density is preserved in interneurons isolated from 129.Scn1a+/- relative to wildtype littermates. This suggests that interneurons from strain 129 compensate for the loss of Nav1.1, while F1 interneurons do not. Based on the strain-dependent difference in phenotypes at the whole animal and cellular levels, we hypothesize that genetic modifiers influence Scn1a+/- phenotype severity due to differences in compensatory capacity among neuronal subtypes in the context of Scn1a heterozygous deletion. We previously mapped several Dravet survival modifier (Dsm) loci that influence premature lethality of Scn1a+/- mice. In the current proposal, we will address our hypothesis in three aims. First, we will perform fine mapping and candidate gene analysis at two Dsm loci on mouse chromosomes 7 and 8. Second, we will perform single cell RNA-seq analysis to characterize differences in cell composition and gene expression in specific cell subpopulations during the critical phase of phenotype onset in epilepsy susceptible F1.Scn1a+/- and resistant 129.Scn1a+/- mice. Third, we will evaluate the modifier potential of candidate genes in vivo using transcriptional modulation to up- and down-regulate candidate gene expression. Results from these studies will identify modifier genes and pathways that influence phenotype severity in Scn1a+/- mice. Identification of modifier genes that influence severity of Dravet syndrome will provide insight into the pathophysiology of epilepsy and will suggest novel therapeutic approaches for improved treatment of human patients.

癫痫是一种常见的神经系统疾病，每26个美国人中就有1人受其影响。SCN1A突变；