Alternative titles; symbols
HGNC Approved Gene Symbol: NOVA1
Cytogenetic location: 14q12 Genomic coordinates (GRCh38): 14:26,443,090-26,598,033 (from NCBI)
Using antisera from patients with a paraneoplastic neurologic disorder involving the subcortical motor system, Buckanovich et al. (1993) identified a gene that they termed NOVA1. The NOVA1 gene encodes a neuron-specific RNA-binding protein that is inhibited by paraneoplastic antibodies (Buckanovich et al., 1996). See also NOVA2 (601991).
To identify Nova RNA targets, Ule et al. (2003) developed a method to purify protein-RNA complexes from mouse brain using ultraviolet crosslinking and immunoprecipitation (CLIP). Thirty-four transcripts were identified multiple times by Nova CLIP. Three-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition. Splicing targets confirmed in Nova-null mice include c-Jun N-terminal kinase-2 (602896), neogenin (601907), and gephyrin (603930); the last encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, 2 previously identified Nova splicing targets. Thus, CLIP revealed that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in paraneoplastic opsoclonus myoclonus ataxia (POMA).
By analyzing alternative splicing in brains of Nova1 -/- and Nova2 -/- mice, Ule et al. (2005) identified Nova-dependent alternatively spliced transcripts. Of the 40 Nova-spliced transcripts with defined brain function, 34 encoded proteins that act at the synapse (neurotransmitter receptors, cation channels, adhesion and scaffold proteins), and 8 encoded proteins involved in axon guidance. Of the 35 proteins with known interaction partners, 26 (74%) interact with each other.
Ule et al. (2006) combined bioinformatics, biochemistry, and genetics to derive an RNA map describing the rules by which Nova proteins regulate alternative splicing. This map revealed that the position of Nova binding sites (YCAY clusters) in a pre-mRNA determines the outcome of splicing. The map correctly predicted Nova's effect to inhibit or enhance exon inclusion, which led Ule et al. (2006) to examine the relationship between the map and Nova's mechanism of action. Nova binding to an exonic YCAY cluster changed the protein complexes assembled on pre-mRNA, blocking U1 snRNP (180740) binding and exon inclusion, whereas Nova binding to an intronic YCAY cluster enhanced spliceosome assembly and exon inclusion. Assays of splicing intermediates of Nova-regulated transcripts in mouse brain revealed that Nova preferentially regulates removal of introns harboring (or closest to) YCAY clusters. Ule et al. (2006) concluded that these results define a genomewide map relating to the position of a cis-acting element to its regulation by an RNA binding protein, namely, that Nova binding to YCAY clusters results in a local and asymmetric action to regulate spliceosome assembly and alternative splicing in neurons.
Licatalosi et al. (2008) developed a genomewide means of mapping protein-RNA binding sites in vivo by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provided genomewide in vivo biochemical footprints confirming the previous prediction that the position of NOVA binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict NOVA action de novo. HITS-CLIP revealed a large number of NOVA-RNA interactions in 3-prime untranslated regions, leading to the discovery that NOVA regulates alternative polyadenylation in the brain. Licatalosi et al. (2008) concluded that HITS-CLIP provides a robust unbiased means to identify functional protein-RNA interactions in vivo.
Prestigiacomo et al. (2001) described a patient with a history of bladder carcinoma (109800) who presented with the opsoclonus-ataxia syndrome. They demonstrated the presence of anti-Ri antibodies in the patient's serum and cerebrospinal fluid and found that the target Ri antigen was expressed in the original tumor specimen. This may have been the first instance of the syndrome with bladder cancer; it has been associated in children with neuroblastoma and in adults with breast carcinoma and gynecologic malignancies.
Fletcher et al. (1997) showed that the mouse homolog maps to mouse chromosome 12 and suggested that the human gene is probably located on 14q.
Jensen et al. (2000) generated Nova1-deficient mice. Homozygous mutant mice are indistinguishable from their wildtype littermates at birth, but die postnatally from a motor deficit associated with apoptotic death of motor neurons in the spinal cord and brainstem. Using histologic stains for a marker expressed in place of Nova1 in the knockout mice, Jensen et al. (2000) confirmed that Nova1 is normally expressed in the ventral spinal cord, brainstem nuclei, deep cerebellar nuclei, and hypothalamus. Using RT-PCR and RNase protection assays, they detected specific splicing defects in Nova1-null mice, including a decrease in utilization of GLRA2 (305990) exon 3A and GABRG2 (137164) exon 9. They observed splicing defects in the brainstem and spinal cord, but not in the forebrain, a region that does not express Nova1. Using mouse brain extracts, they demonstrated that Nova1 specifically binds to the GLRA2 intronic (UCAUY)3 sequence motif. They concluded that Nova1 is essential for postnatal motor neuron survival, where it binds RNA in a sequence-specific manner to regulate neuron-specific splicing of inhibitory receptor pre-mRNAs.
Buckanovich, R. J., Posner, J. B., Darnell, R. B. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11: 657-672, 1993. [PubMed: 8398153] [Full Text: https://doi.org/10.1016/0896-6273(93)90077-5]
Buckanovich, R. J., Yang, Y. Y., Darnell, R. B. The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies. J. Neurosci. 16: 1114-1122, 1996. [PubMed: 8558240] [Full Text: https://doi.org/10.1523/JNEUROSCI.16-03-01114.1996]
Fletcher, C. F., Okano, H. J., Gilbert, D. J., Yang, Y., Yang, C., Copeland, N. G., Jenkins, N. A., Darnell, R. B. Mouse chromosomal locations of nine genes encoding homologs of human paraneoplastic neurologic disorder antigens. Genomics 45: 313-319, 1997. [PubMed: 9344654] [Full Text: https://doi.org/10.1006/geno.1997.4925]
Jensen, K. B., Dredge, B. K., Stefani, G., Zhong, R., Buckanovich, R. J., Okano, H. J., Yang, Y. Y. L., Darnell, R. B. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25: 359-371, 2000. [PubMed: 10719891] [Full Text: https://doi.org/10.1016/s0896-6273(00)80900-9]
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., Darnell, J. C., Darnell, R. B. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456: 464-469, 2008. [PubMed: 18978773] [Full Text: https://doi.org/10.1038/nature07488]
Prestigiacomo, C. J., Balmaceda, C., Dalmau, J. Anti-Ri-associated paraneoplastic opsoclonus-ataxia syndrome in a man with transitional cell carcinoma: a case report. Cancer 91: 1423-1428, 2001. [PubMed: 11301388] [Full Text: https://doi.org/10.1002/1097-0142(20010415)91:8<1423::aid-cncr1148>3.0.co;2-f]
Ule, J., Jensen, K. B., Ruggiu, M., Mele, A., Ule, A., Darnell, R. B. CLIP identifies Nova-regulated RNA networks in the brain. Science 302: 1212-1215, 2003. [PubMed: 14615540] [Full Text: https://doi.org/10.1126/science.1090095]
Ule, J., Stefani, G., Mele, A., Ruggiu, M., Wang, X., Taneri, B., Gaasterland, T., Blencowe, B. J., Darnell, R. B. An RNA map predicting Nova-dependent splicing regulation. Nature 444: 580-586, 2006. [PubMed: 17065982] [Full Text: https://doi.org/10.1038/nature05304]
Ule, J., Ule, A., Spencer, J., Williams, A., Hu, J.-S., Cline, M., Wang, H., Clark, T., Fraser, C., Ruggiu, M., Zeeberg, B. R., Kane, D., Weinstein, J. N., Blume, J., Darnell, R. B. Nova regulates brain-specific splicing to shape the synapse. Nature Genet. 37: 844-852, 2005. [PubMed: 16041372] [Full Text: https://doi.org/10.1038/ng1610]