Abstract
Nova-1, a protein expressed in tumors and neurons, is a target antigen in a human paraneoplastic motor disorder [paraneoplastic opsoclonus-myoclonus ataxia (POMA)]. We evaluated the relationship between the function 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 nervous 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 domain but not an inactive point mutant, and affinity-purified antibody blocks Nova-1 RNA binding. Thus, a cardinal feature of POMA is the production of antibodies that inhibit Nova-1-RNA interactions, suggesting such inhibition may cause the neurological disease.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Neoplasm / immunology*
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Antigens, Neoplasm / chemistry
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / physiology*
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Ataxia / etiology
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Ataxia / immunology*
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Autoantibodies / immunology*
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Autoimmune Diseases / immunology
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Brain Chemistry
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Consensus Sequence
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Epitopes / immunology
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Humans
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Mice
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Molecular Sequence Data
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Myoclonus / etiology
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Myoclonus / immunology*
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Neoplasms / complications
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Neoplasms / immunology
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / physiology*
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Neuro-Oncological Ventral Antigen
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Neurons / metabolism*
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Ocular Motility Disorders / etiology
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Ocular Motility Disorders / immunology*
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Paraneoplastic Syndromes / immunology*
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Point Mutation
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Protein Binding
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Protein Structure, Tertiary
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / chemistry
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / immunology
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RNA-Binding Proteins / physiology*
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Ribonucleoproteins / antagonists & inhibitors
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Ribonucleoproteins / chemistry
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Ribonucleoproteins / genetics
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Ribonucleoproteins / immunology
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Ribonucleoproteins / physiology*
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Sequence Alignment
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Sequence Homology, Amino Acid
Substances
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Antibodies, Neoplasm
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Antigens, Neoplasm
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Autoantibodies
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Epitopes
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Nerve Tissue Proteins
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Neuro-Oncological Ventral Antigen
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RNA-Binding Proteins
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Ribonucleoproteins