The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation - Université de Montpellier Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2014

The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation

Jaeho Lee
  • Fonction : Auteur
Cari Sagum
  • Fonction : Auteur
Muhammad Mahajnah
  • Fonction : Auteur
Rajech Sharkia
  • Fonction : Auteur
Fabrice Klein
  • Fonction : Auteur
Mark Bedford
  • Fonction : Auteur
Peter Bauer
  • Fonction : Auteur
C. Marcelo Aldaz
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-02434727 , version 1 (10-01-2020)

Identifiants

Citer

Martial Mallaret, Matthis Synofzik, Jaeho Lee, Cari Sagum, Muhammad Mahajnah, et al.. The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation. Brain - A Journal of Neurology , 2014, 137 (2), pp.411-419. ⟨10.1093/brain/awt338⟩. ⟨hal-02434727⟩
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