WWOX Mutation, a Newly Discovered Cause for Brain Developmental Disorders

The WW domain-containing oxidoreductase (WWOX/WOX1/FOR) gene maps to chromosomal fragile site FRA16D, and behaves as a tumor suppressor. WWOX functions as an adapter protein regulating ATM and BRCA1. More recently, missense and nonsense mutations in WWOX have been identified in the context of central nervous system (CNS)-related disorders. Structural and functional WWOX abnormalities have been identified in a number of different families. The patients described span a wide range of neurological severity, ranging from seizure disorder associated with global developmental delay, progressive microcephaly, bilateral optic atrophy, and spastic quadriplegia in very young age children (as early as 1.5 months) – recently termed WOREE phenotype, for WWOX-Related Epileptic Encephalopathy - to non-progressive microcephaly and less severe phenotype in adolescence-adult with later onset at 9-12 months – associated with spinocerebellar ataxia type 12 (SCAR12). This wide range of phenotypic abnormalities could be due to the nature of these mutations. Relatively milder phenotypes seem to origin from missense point mutations (P47T & P47R, G372R) while severe manifestations were observed in nonsense mutation (R54*, K297* and W335*) or partial-to-complete deletions. Consistent with these observations in human patients, we found that Wwox-null mice display spontaneous seizures, growth retardation, hypoglycemia and premature death by the age of 3-4 weeks. Modeling somatic loss of WWOX expression in neural stem cells (using Nestin-Cre) and mature neurons (using Synapsin-I-Cre) resulted in a phenotype that is reminiscent of the Wwox null mouse phenotype. Transcriptomic analysis of hippocampal neurons revealed impaired expression of mature oligodendrocyte markers and defects in myelination. Our results suggest that the gene product of FRAD16 common fragile site has direct roles in neuronal homeostasis and that its loss is associated with neuropathy.