title: Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy.
abstract: OBJECTIVE
  Voltage-gated sodium channel (Nav)-encoding genes are among early-onset epileptic encephalopathies (EOEE) targets, suggesting that other genes encoding Nav-binding proteins, such as fibroblast growth factor homologous factors (FHFs), may also play roles in these disorders.
  
  
  METHODS
  To identify additional genes for EOEE, we performed whole-exome sequencing in a family quintet with 2 siblings with a lethal disease characterized by EOEE and cerebellar atrophy. The pathogenic nature and functional consequences of the identified sequence alteration were determined by electrophysiologic studies in vitro and in vivo.
  
  
  RESULTS
  A de novo heterozygous missense mutation was identified in the FHF1 gene (FHF1AR114H, FHF1BR52H) in the 2 affected siblings. The mutant FHF1 proteins had a strong gain-of-function phenotype in transfected Neuro2A cells, enhancing the depolarizing shifts in Nav1.6 voltage-dependent fast inactivation, predicting increased neuronal excitability. Surprisingly, the gain-of-function effect is predicted to result from weaker interaction of mutant FHF1 with the Nav cytoplasmic tail. Transgenic overexpression of mutant FHF1B in zebrafish larvae enhanced epileptiform discharges, demonstrating the epileptic potential of this FHF1 mutation in the affected children.
  
  
  CONCLUSIONS
  Our data demonstrate that gain-of-function FHF mutations can cause neurologic disorder, and expand the repertoire of genetic causes (FHF1) and mechanisms (altered Nav gating) underlying EOEE and cerebellar atrophy.
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Siekierska
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Mala
authors.initials: M
authors.lastname: Isrie
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Chloë
authors.initials: C
authors.lastname: Scheldeman
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Niels
authors.initials: N
authors.lastname: Vanthillo
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Peter A M
authors.initials: PA
authors.lastname: de Witte
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldfarb
authors.affiliation: From the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences (A.S., C.S., N.V., P.A.M.d.W.), and Laboratory for the Genetics of Cognition (M.I.), University of Leuven; Center for Human Genetics (M.I., H.V.E.) and Child Neurology (L.L., G.M.B.), University Hospitals Leuven; Department of Biological Sciences (Y.L., M.G.), Hunter College of City University, New York; and Graduate Program in Biology/Neuroscience at City University (Y.L.), New York, NY. gunnar.buyse@uzleuven.be.
authors.forename: Gunnar M
authors.initials: GM
authors.lastname: Buyse
mesh_terms: D017668:Age of Onset; D000818:Animals; D030801:Animals, Genetically Modified; D001284:Atrophy; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D045744:Cell Line, Tumor; D002526:Cerebellar Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D017809:Fatal Outcome; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D035781:Siblings; D015027:Zebrafish
chemical_list: C486356:FGF12 protein, human; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491046:Scn8a protein, mouse; D005346:Fibroblast Growth Factors