RBFOX1 and RBFOX3 mutations in rolandic epilepsy.

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...

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Autores principales: Dennis Lal, Eva M Reinthaler, Janine Altmüller, Mohammad R Toliat, Holger Thiele, Peter Nürnberg, Holger Lerche, Andreas Hahn, Rikke S Møller, Hiltrud Muhle, Thomas Sander, Fritz Zimprich, Bernd A Neubauer
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:c75163a24f994194b80d2d5d069360962021-11-18T08:56:32ZRBFOX1 and RBFOX3 mutations in rolandic epilepsy.1932-620310.1371/journal.pone.0073323https://doaj.org/article/c75163a24f994194b80d2d5d069360962013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24039908/?tool=EBIhttps://doaj.org/toc/1932-6203Partial 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.Dennis LalEva M ReinthalerJanine AltmüllerMohammad R ToliatHolger ThielePeter NürnbergHolger LercheAndreas HahnRikke S MøllerHiltrud MuhleThomas SanderFritz ZimprichBernd A NeubauerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 9, p e73323 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Dennis Lal
Eva M Reinthaler
Janine Altmüller
Mohammad R Toliat
Holger Thiele
Peter Nürnberg
Holger Lerche
Andreas Hahn
Rikke S Møller
Hiltrud Muhle
Thomas Sander
Fritz Zimprich
Bernd A Neubauer
RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
description 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.
format article
author Dennis Lal
Eva M Reinthaler
Janine Altmüller
Mohammad R Toliat
Holger Thiele
Peter Nürnberg
Holger Lerche
Andreas Hahn
Rikke S Møller
Hiltrud Muhle
Thomas Sander
Fritz Zimprich
Bernd A Neubauer
author_facet Dennis Lal
Eva M Reinthaler
Janine Altmüller
Mohammad R Toliat
Holger Thiele
Peter Nürnberg
Holger Lerche
Andreas Hahn
Rikke S Møller
Hiltrud Muhle
Thomas Sander
Fritz Zimprich
Bernd A Neubauer
author_sort Dennis Lal
title RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
title_short RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
title_full RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
title_fullStr RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
title_full_unstemmed RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
title_sort rbfox1 and rbfox3 mutations in rolandic epilepsy.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/c75163a24f994194b80d2d5d06936096
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