title: RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
abstract: Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365 kb deletion affecting two untranslated 5'-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany ; Department of Neuropediatrics, University Medical Clinic Giessen, Giessen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.forename: Eva M
authors.initials: EM
authors.lastname: Reinthaler
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D019305:Epilepsy, Rolandic / Q000235:genetics*; D005091:Exons; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; D009419:Nerve Tissue Proteins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C506808:neuronal nuclear antigen NeuN, human
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