The WWOX gene (WW Domain Containing Oxidoreductase), also known as FOR or WOX1, encodes a tumor suppressor protein with two WW domains and a short-chain dehydrogenase/reductase domain. Biallelic WWOX mutations cause autosomal recessive spinocerebellar ataxia type 12 (SCAR12). WWOX plays important roles in neuronal development, synaptic function, and response to oxidative stress.
WWOX contains two WW domains that bind proline-rich motifs in target proteins, and an SDR domain with oxidoreductase activity. WWOX interacts with p53, Apc, and transcription factors, modulating their stability. In neurons, it is involved in synaptic vesicle trafficking, neurotransmitter release, mitochondrial function, and apoptosis regulation.
Biallelic WWOX mutations cause SCAR12 (early-onset cerebellar ataxia, developmental delay, seizures). WWOX haploinsufficiency is associated with epilepsy, autism, and intellectual disability. As a tumor suppressor, WWOX loss promotes cancer progression. WWOX may interact with AD/PD-related proteins in neurodegeneration.
WWOX is widely expressed with high levels in brain (cerebellum, cortex, hippocampus). In neurons, it localizes to cytoplasm, synaptic vesicles, and mitochondria. Highest expression during development, declining in adulthood.