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

MALLARET, Martial ; SYNOFZIK, Matthis ; TRANCHANT, Christine ; MIGNOT, Cyril ; MANDEL, Jean-Louis ; BEDFORD, Mark ; BAUER, Peter ; SALIH, Mustafa A ; SCHÜLE, Rebecca ; SCHÖLS, Ludger ; ALDAZ, C. Marcelo ; KOENIG, Michel ; JAEHO LEE ; SAGUM, Cari A ; MAHAJNAH, Muhammad ; SHARKIA, Rajech ; DROUOT, Nathalie ; RENAUD, Mathilde ; KLEIN, Fabrice A. C ; ANHEIM, Mathieu

Brain (London, England : 1878), 2014-02, Vol.137 (Pt 2), p.411-419 [Revista revisada por pares]

Oxford: Oxford University Press

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The tumour suppressor gene WWOX is mutated in autosomal recessive cerebellar ataxia with epilepsy and mental retardation
Autor: MALLARET, Martial ; SYNOFZIK, Matthis ; TRANCHANT, Christine ; MIGNOT, Cyril ; MANDEL, Jean-Louis ; BEDFORD, Mark ; BAUER, Peter ; SALIH, Mustafa A ; SCHÜLE, Rebecca ; SCHÖLS, Ludger ; ALDAZ, C. Marcelo ; KOENIG, Michel ; JAEHO LEE ; SAGUM, Cari A ; MAHAJNAH, Muhammad ; SHARKIA, Rajech ; DROUOT, Nathalie ; RENAUD, Mathilde ; KLEIN, Fabrice A. C ; ANHEIM, Mathieu
Materias: Adolescent ; Adult ; Adult and adolescent clinical studies ; Amino Acid Sequence ; Animals ; Biological and medical sciences ; Cells, Cultured ; Cerebellar Ataxia - diagnosis ; Cerebellar Ataxia - epidemiology ; Cerebellar Ataxia - genetics ; Cerebrospinal fluid. Meninges. Spinal cord ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Epilepsy - diagnosis ; Epilepsy - epidemiology ; Epilepsy - genetics ; Female ; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy ; Humans ; Intellectual deficiency ; Intellectual Disability - diagnosis ; Intellectual Disability - epidemiology ; Intellectual Disability - genetics ; Life Sciences ; Male ; Medical sciences ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Mutation, Missense - genetics ; Nervous system (semeiology, syndromes) ; Neurology ; Original ; Oxidoreductases - genetics ; Pedigree ; Polymorphism, Single Nucleotide ; Protein Structure, Secondary ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Saudi Arabia - epidemiology ; Tumor Suppressor Proteins - genetics ; WW Domain-Containing Oxidoreductase ; Young Adult
Es parte de: Brain (London, England : 1878), 2014-02, Vol.137 (Pt 2), p.411-419
Notas: ObjectType-Article-1
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PMCID: PMC3914474
These authors contributed equally to this work.
Descripción: 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.
Editor: Oxford: Oxford University Press
Idioma: Inglés

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

Oxford: Oxford University Press

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