Alternative titles; symbols
HGNC Approved Gene Symbol: ELAVL4
Cytogenetic location: 1p33-p32.3 Genomic coordinates (GRCh38): 1:50,048,055-50,203,772 (from NCBI)
Paraneoplastic encephalomyelitis with sensory neuropathy is a disorder of the nervous system associated with small-cell lung cancer and is characterized by dementia, sensory loss, and other neurologic disabilities. The pathology is typical of an autoimmune disease and is distinguished by neuronal loss and inflammatory infiltrates. Sera from a high percentage of such patients contain a high titer of antibodies that react with a group of antigens expressed in neurons and small-cell lung tumors. Szabo et al. (1991) isolated cDNA clones encoding a specific gene product, designated HuD. The gene encoding the HuD protein has homologies with 2 Drosophila genes, 'embryonic lethal abnormal vision,' or elav (see ELAVL2, 601673, and Robinow et al. (1988)), and 'sex lethal' (Bell et al., 1988), which have well-established roles in the maturation of Drosophila neurons and in fruit fly sex determination. Levine et al. (1993) isolated an autoimmune RNA-binding protein that was shown to be the human homolog of elav and to be reactive with autoantibodies from patients with paraneoplastic encephalomyelitis.
Levine et al. (1993) showed that ELAVL4 has specificity for 3-prime uridylate-rich untranslated regions of growth factor mRNAs.
King et al. (1994) identified a potential link between the neuronal 3-prime UTR RNA-binding protein ELAVL4 and regulatory transcription factors involved in neural development.
Chagnovich and Cohn (1996) found that expression of a 40-kD protein (p40) in a human neuroblastoma cell line correlated with increased half-life of MYCN (164840) mRNA and increased MYCN expression. This protein bound to 2 distinct AU-rich regions of the 3-prime UTR of MYCN. p40 activity was detected in 5 of 19 primary neuroblastomas, and the activity was associated with clinically aggressive disease. Chagnovich et al. (1996) determined that p40 is an ELAV, and they concluded that it is likely HUD, since this was the only ELAV differentially expressed in the neuroblastoma cell line investigated. Chagnovich et al. (1996) found that purified HUD and ELAVL2 bound with high specificity to the same 3-prime sequences of MYCN.
Manohar et al. (2002) identified at least 4 cis-acting destabilizing elements within the MYCN 3-prime UTR, and they found that HUD binding to this region stabilized MYCN mRNA in cells. Ectopic overexpression of HUD in mouse fibroblasts dramatically inhibited decay of a reporter RNA fused to either full-length MYCN 3-prime UTR or to cis-acting destabilizing elements harboring HUD-binding sites. Manohar et al. (2002) suggested that HUD may contribute to the malignant phenotype of neuroblastoma cells by stabilizing MYCN mRNA, thereby enhancing steady-state levels of expression of this oncogene.
By in situ hybridization, Muresu et al. (1994) demonstrated that the human PNEM gene is located at 1p34.
The paraneoplastic neurologic disorders (PND) are a rare group of neurologic syndromes that arise when an immune response to systemic tumors expressing neuronal proteins ('onconeural antigens') develops into an autoimmune neuronal degeneration. The use of patient antisera to clone the genes encoding PND antigens led to new insight into the mechanism of these autoimmune disorders. The tumor antigens can be grouped into 3 classes: (1) neuron-specific RNA-binding proteins, (2) nerve terminal vesicle-associated proteins, and (3) cytoplasmic signaling proteins. Fletcher et al. (1997) determined the mouse chromosomal locations of 4 genes in the first of these 3 classes: Hua, Hub (601673), Huc (603458), and Hud. Hua was found to be located on mouse chromosome 8 very close to the insulin gene (176730) which is on human 19p13.3. Hub was mapped to mouse chromosome 4 close to the interferon alpha gene (147660) which had been mapped to human 9p22; the human Hub homolog had been mapped to 9p21. The mouse Huc gene was mapped to chromosome 9 close to the Epor gene whose human homolog is located on 19p13.2 (133171). The Hud gene was located on chromosome 4 in a region consistent with its mapping to human 1p34. The data suggested that the Hua-Hud genes arose through gene duplication and dispersion. They raised the possibility that the HuD gene may be the site of mutation underlying Charcot-Marie-tooth disease, CMT2A (see 118210), which maps to 1p36-p35.
For discussion of a possible association between variation in the ELAVL4 gene and Parkinson disease, see PARK10 (606852).
Akamatsu et al. (2005) found that Hud-null mice were born at the expected mendelian ratio. While there was a transient delay in neurite extension in mutant embryos, Hud-null pups were indistinguishable from their wildtype littermates for the first several postnatal weeks. Adult animals, however, developed an abnormal hind-limb clasping reflex and showed poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of neural stem/progenitor cells were increased in Hud-deficient mice. The cerebral wall of mutant embryos had a reduced number of differentiating quiescent cells, and there was an increase in slowly-dividing stem cells in the subventricular zone of mutant adults. Akamatsu et al. (2005) concluded that HUD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.
Akamatsu, W., Fujihara, H., Mitsuhashi, T., Yano, M., Shibata, S., Hayakawa, Y., Okano, H. J., Sakakibara, S., Takano, H., Takano, T., Takahashi, T., Noda, T., Okano, H. The RNA-binding protein HuD regulates neuronal cell identity and maturation. Proc. Nat. Acad. Sci. 102: 4625-4630, 2005. [PubMed: 15764704] [Full Text: https://doi.org/10.1073/pnas.0407523102]
Bell, L. R., Maine, E. M., Schedl, P., Cline, T. W. Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins. Cell 55: 1037-1046, 1988. [PubMed: 3144435] [Full Text: https://doi.org/10.1016/0092-8674(88)90248-6]
Chagnovich, D., Cohn, S. L. Binding of a 40-kDa protein to the N-myc 3-prime-untranslated region correlates with enhanced N-myc expression in human neuroblastoma. J. Biol. Chem. 271: 33580-33586, 1996. [PubMed: 8969225] [Full Text: https://doi.org/10.1074/jbc.271.52.33580]
Chagnovich, D., Fayos, B. E., Cohn, S. L. Differential activity of ELAV-like RNA-binding proteins in human neuroblastoma. J. Biol. Chem. 271: 33587-33591, 1996. [PubMed: 8969226] [Full Text: https://doi.org/10.1074/jbc.271.52.33587]
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]
King, P. H., Levine, T. D., Fremeau, R. T., Jr., Keene, J. D. Mammalian homologs of Drosophila elav localized to a neuronal subset can bind in vitro to the 3-prime UTR of mRNA encoding the Id transcriptional repressor. J. Neurosci. 14: 1943-1952, 1994. [PubMed: 8158249] [Full Text: https://doi.org/10.1523/JNEUROSCI.14-04-01943.1994]
Levine, T. D., Gao, F., King, P. H., Andrews, L. G., Keene, J. D. He1-N1: an autoimmune RNA-binding protein with specificity for 3-prime uridylate-rich untranslated regions of growth factor mRNAs. Molec. Cell. Biol. 13: 3494-3504, 1993. [PubMed: 8497264] [Full Text: https://doi.org/10.1128/mcb.13.6.3494-3504.1993]
Manohar, C. F., Short, M. L., Nguyen, A., Nguyen, N. N., Chagnovich, D., Yang, Q., Cohn, S. L. HuD, a neuronal-specific RNA-binding protein, increases the in vivo stability of MYCN RNA. J. Biol. Chem. 277: 1967-1973, 2002. [PubMed: 11711535] [Full Text: https://doi.org/10.1074/jbc.M106966200]
Muresu, R., Baldini, A., Gress, T., Posner, J. B., Furneaux, H. M., Siniscalco, M. Mapping of the gene coding for a paraneoplastic encephalomyelitis antigen (HuD) to human chromosome site 1p34. Cytogenet. Cell Genet. 65: 177-178, 1994. [PubMed: 8222755] [Full Text: https://doi.org/10.1159/000133626]
Robinow, S., Campos, A. R., Yao, K.-M., White, K. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs. Science 242: 1570-1572, 1988. Note: Erratum: Science 243: 12 only, 1989. [PubMed: 3144044] [Full Text: https://doi.org/10.1126/science.3144044]
Szabo, A., Dalmau, J., Manley, G., Rosenfeld, M., Wong, E., Henson, J., Posner, J. B., Furneaux, H. M. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to elav and sex-lethal. Cell 67: 325-333, 1991. [PubMed: 1655278] [Full Text: https://doi.org/10.1016/0092-8674(91)90184-z]