THE ONCONEURAL ANTIGEN NOVA-1 IS A NEURON-SPECIFIC RNA-BINDING PROTEIN, THE ACTIVITY OF WHICH IS INHIBITED BY PARANEOPLASTIC ANTIBODIES

Nova-1, a protein expressed in tumors and neurons, is a target antigen in a human paraneoplastic motor disorder [paraneoplastic opsoclonus-m yoclonus ataxia (POMA)]. We evaluated the relationship between the fun ction of Nova-1 and its role as a disease antigen. We show that Nova-1 is a neuron-specific RNA-binding protein with sequence and functional similarities to FMR-1. Nova-1 mRNA is restricted to the subcortical n ervous system, and the protein binds to RNA with high affinity. Nova-1 KH domains mediate this RNA binding, and point mutations within them abrogate binding. POMA disease antisera (6/6) recognize the third KH d omain but not an inactive point mutant, and affinity-purified antibody blocks Nova-1 RNA binding. Thus, a cardinal feature of POMA is the pr oduction of antibodies that inhibit Nova-1-RNA interactions, suggestin g such inhibition may cause the neurological disease.