RBFOX1 and RBFOX3 Mutations in Rolandic Epilepsy
Open accessAbstract
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.
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Human mutations in RBFOX1 have been identified in patients with epilepsy.
“Human mutations in RBFOX1 have been identified in patients with epilepsy126–128”
From The neurogenetics of alternative splicing (2016) · cites this paper as [127]
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The neurogenetics of alternative splicing
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- Authors
- Lal, D., Reinthaler, E. M., Altmüller, J., Toliat, M. R., Thiele, H., Nürnberg, P., Lerche, H., Hahn, A., Møller, R. S., Muhle, H., Sander, T., Zimprich, F., & Neubauer, B. A.
- Affiliations
- University of Cologne (DE)
- Medical University of Vienna (AT)
- Hertie Institute for Clinical Brain Research (DE)
- Justus-Liebig-Universität Gießen (DE)
- The Danish Epilepsy Association (DK)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Neubauer, Bernd A.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-06
- Volume
- 8
- Issue
- 9
- Pages
- e73323
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3765197
- OpenAlex
- W2023519504
- Cited by
- 113
- References
- 33
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 10 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 3 · 2018: 11 · 2017: 10 · 2016: 12 · 2015: 10 · 2014: 12 · 2013: 2
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Update notices
- correction (2013-10-29)
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- European Science Foundation (NU50/8-1, SA434/5-1, BN416/5-1)
- National Institutes of Health (1rc2hl103010-01)
- National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, UC2HL102925, HL 103010, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- RBFOX1, NeuN, RBFOX2, rolandic epilepsy, alternative splicing, hemizygous deletion, novel variants, nonsense mutation, frameshift mutation, genetic susceptibility, neurodevelopmental disorders
- MeSH terms
- RNA Splicing Factors, Exons, Humans, Mutation, Nerve Tissue Proteins, Pedigree, RNA-Binding Proteins, Epilepsy, Rolandic, Antigens, Nuclear
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