CNTNAP2: isoform- and context-specific functions in neurological disorders and cancer

Contactin-associated protein-like 2 (CNTNAP2) is one of the largest and most evolutionarily conserved genes in the human genome that increasingly recognized as a pleiotropic and context-dependent regulator of human disorders. Genetic, immunological, and transcriptomic studies have implicated CNTNAP2 in a broad spectrum of neurological and psychiatric disorders, autoimmune encephalitis, and cancer. Early work focused primarily on the full-length isoform CNTNAP2-201, which encodes CASPR2 or CNTNAP2, and plays essential roles in neuronal development, axon-glia interactions, synaptic transmission, interneuron maturation, and maintenance of excitatory-inhibitory balance. Disruption of these functions contributes to impaired cortical connectivity and network dysfunction in neurodevelopmental disorders. Recent discoveries have substantially expanded this view by revealing isoform-specific and proteolytic fragment-dependent functions of CNTNAP2. Proteolytic processing of CNTNAP2 generates bioactive extracellular and intracellular fragments that regulate calcium homeostasis, gene expression, and neuronal network activity. In parallel, the short isoform CNTNAP2-203 has recently emerged as an oncogenic driver in oral squamous cell carcinoma, where its selective upregulation amplifies EGFR-E2F1 signaling and promotes tumor progression. This review synthesizes current knowledge of CNTNAP2 biology, highlighting isoform- and context-specific mechanisms and outlining key unanswered questions relevant to both neurological disease and cancer.