Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects

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.

Automated summary

WWOX-related epileptic encephalopathy (WOREE) syndrome is a neurodevelopmental disorder caused by bi-allelic mutations in the WWOX gene, leading to symptoms such as intractable epilepsy and developmental delay. Studies in mice and human brain organoids have shown evidence of myelination defects and hyperexcitability associated with WWOX function.