title: The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation.
abstract: 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.
authors.affiliation: 1 Department of Neurology, Hôpital de Hautepierre, Strasbourg, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Mallaret
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.forename: Jaeho
authors.initials: J
authors.lastname: Lee
authors.forename: Cari A
authors.initials: CA
authors.lastname: Sagum
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mahajnah
authors.forename: Rajech
authors.initials: R
authors.lastname: Sharkia
authors.forename: Nathalie
authors.initials: N
authors.lastname: Drouot
authors.forename: Mathilde
authors.initials: M
authors.lastname: Renaud
authors.forename: Fabrice A C
authors.initials: FA
authors.lastname: Klein
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Mark
authors.initials: M
authors.lastname: Bedford
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Aldaz
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D004827:Epilepsy / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D012529:Saudi Arabia / Q000453:epidemiology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human
keywords: WW domain; WWOX; ataxia; hereditary spastic paraplegia; tonic-clonic epilepsy