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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation
Brain, Volume 137, No. 2, Year 2014
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Description
We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy. © 2013 The Author (2013).
Authors & Co-Authors
Mallaret, M.
France, Strasbourg
Hopital de Hautepierre
France, Strasbourg
Université de Strasbourg
Synofzik, Matthis
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Lee, Jaeho
United States, Houston
The University of Texas Md Anderson Cancer Center
Sagum, Cari A.
United States, Houston
The University of Texas Md Anderson Cancer Center
Mahajnah, Muhammad
Israel, Hadera
Hillel Yaffe Medical Center
Israel, Haifa
Technion - Israel Institute of Technology
Sharkia, Rajech
Israel, Beit Berl
Beit Berl Academic College
Drouot, Nathalie
France, Strasbourg
Université de Strasbourg
Renaud, Mathilde
France, Strasbourg
Hopital de Hautepierre
France, Strasbourg
Université de Strasbourg
Klein, Fabrice A.C.
France, Strasbourg
Université de Strasbourg
Anheim, Mathieu
France, Strasbourg
Hopital de Hautepierre
France, Strasbourg
Université de Strasbourg
Tranchant, Christine H.
France, Strasbourg
Hopital de Hautepierre
France, Strasbourg
Université de Strasbourg
Mignot, Cyril
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
Mandel, Jean Louis
France, Strasbourg
Université de Strasbourg
France, Strasbourg
Hopital Civil
Bedford, Mark T.
United States, Houston
The University of Texas Md Anderson Cancer Center
Bauer, Peter
Germany, Tubingen
Eberhard Karls Universität Tübingen
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
College of Medicine
Schüle, Rebecca
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
United States, Miami
University of Miami Leonard M. Miller School of Medicine
Schöls, Ludger
Germany, Tubingen
Hertie-institut Für Klinische Hirnforschung
Germany, Bonn
Deutsches Zentrum Für Neurodegenerative Erkrankungen
Aldaz, C. Marcelo
United States, Houston
The University of Texas Md Anderson Cancer Center
Kœnig, Michel
France, Strasbourg
Université de Strasbourg
France, Strasbourg
Hopital Civil
France, Montpellier
Centre Hospitalier Universitaire de Montpellier
Statistics
Citations: 106
Authors: 20
Affiliations: 14
Identifiers
Doi:
10.1093/brain/awt338
e-ISSN:
14602156
Research Areas
Cancer
Genetics And Genomics