Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects.
Brain
; 144(10): 3061-3077, 2021 11 29.
Article
em En
| MEDLINE
| ID: mdl-33914858
ABSTRACT
WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Deleção de Genes
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Epilepsia
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Oxidorredutase com Domínios WW
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Bainha de Mielina
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Neurônios
Tipo de estudo:
Etiology_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article