Document text
Principal Investigator: Jennifer A Kearney
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $472,020
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <129 Mouse><Address><Affect><Age><Age Months><Alleles><Allelic Loss><Allelomorphs><American><Ammon Horn><Animals><Behavioral><Brain><Brain Nervous System><Buffers><Candidate Disease Gene><Candidate Gene><Causality><Cell Body><Cells><Chromosome 7><Chromosome 8><Chromosomes><Clinical><Code><Coding System><Cognitive><Compensation><Complex><Congenic Strain><Connector Neuron><Cornu Ammonis><DNA><Data><Data Set><Deoxyribonucleic Acid><Development><Developmental Delay><Developmental Delay Disorders><Disease><Disorder><Dysfunction><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Etiology><Evaluation><Exhibits><Failure><Febrile Convulsion Seizure><Febrile Convulsions><Febrile Fit><Febrile Seizures><Fever Convulsion><Fever Seizure><Functional disorder><Gene Expression><Gene Modified><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic defect><Genetic propensity><Goals><Hereditary><Heterozygote><Hippocampus><Human><Individual><Infant><Inherited><Inherited Predisposition><Inherited Susceptibility><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Ion Channel><Ionic Channels><Loss of Heterozygosity><Maps><Medicine><Membrane Channels><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Na element><Na(v)1.1><Nav1.1><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic><Neurologic Disorders><Neurological><Neurological Disorders><Neuronal Transmission><Neurons><Pathogenicity><Pathway interactions><Patients><Pedigree><Persons><Phase><Phenotype><Physiopathology><Population><Predisposition><Proteins><Pyrexial Convulsion><Pyrexial Seizure><QTL><QTL Genes><Quantitative Trait Loci><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Refractory><Reporting><Resistance><Resolution><Risk><Risk-associated variant><SCN1A protein><SUDEP><Seizure Disorder><Seizures><Severities><Severity of illness><Single-Nucleus Sequencing><Sodium><Sodium Channel><Sodium Ion Channels><Specific Child Development Disorders><Survey Instrument><Surveys><Susceptibility><Synapses><Synaptic><Syndrome><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Variant><Variation><ages><axon signaling><axon-glial signaling><axonal signaling><causation><cell type><childhood epilepsy><death risk><density><developmental><differential expression><differentially expressed><disease causation><disease severity><dravet syndrome><epilepsia><epileptic encephalopathies><epileptogenic><gene modification><genetic etiology><genetic mechanism of disease><genetic pedigree><genetic vulnerability><genetically modified><genetically predisposed><genome mutation><glia signaling><glial signaling><heterozygosity><hippocampal><improved><in vivo><insight><intellectual and developmental disability><life span><lifespan><limited intellectual functioning><loss of function><loss of function mutation><mortality risk><nerve signaling><neural signaling><neurological disease><neuronal><neuronal signaling><neurotransmission><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pathway><pediatric epilepsy><pedigree structure><permissiveness><premature><prematurity><preservation><promoter><promotor><resistant><resolutions><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><scRNA-seq><severe myoclonic epilepsy of infancy><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><sudden unexpected death in epilepsy><synapse><therapeutic target><trait><transcriptional differences><transcriptome sequencing><transcriptomic sequencing><voltage>