title: Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.
abstract: We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability.
authors.affiliation: Department of Neurobiology, Department of Neurology.
authors.forename: Ram S
authors.identifier: http://orcid.org/0000-0003-4383-3849
authors.initials: RS
authors.lastname: Puranam
authors.affiliation: Department of Neurobiology, Department of Neurology.
authors.forename: Xiao Ping
authors.initials: XP
authors.lastname: He
authors.affiliation: Department of Neurobiology.
authors.forename: Lijun
authors.initials: L
authors.lastname: Yao
authors.affiliation: Duke University School of Medicine.
authors.forename: Tri
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Neurobiology.
authors.forename: Wonjo
authors.initials: W
authors.lastname: Jang
authors.affiliation: Department of Pathology.
authors.forename: Catherine W
authors.initials: CW
authors.lastname: Rehder
authors.affiliation: Department of Pediatrics (Neurology), and.
authors.forename: Darrell V
authors.identifier: http://orcid.org/0000-0003-2917-7822
authors.initials: DV
authors.lastname: Lewis
authors.affiliation: Department of Neurobiology, Department of Neurology, Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina 27710 jmc@neuro.duke.edu.
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005334:Fever / Q000150:complications; D005346:Fibroblast Growth Factors / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D003294:Seizures, Febrile / Q000209:etiology / Q000235:genetics; D012737:Sex Factors; D013569:Synapses / Q000235:genetics*; D055366:Synaptic Potentials / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics; D014960:X Chromosome / Q000235:genetics; D055815:Young Adult
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors
keywords: Fgf13; GEFS+; animal model; epilepsy; excitatory inhibitory imbalance; translocation