Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ELP4
SNOMEDCT: 69278003; ICD10CM: Q13.1; ICD9CM: 743.45;
Cytogenetic location: 11p13 Genomic coordinates (GRCh38): 11:31,509,767-31,790,324 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | ?Aniridia 2 | 617141 | Autosomal dominant | 3 |
The yeast Elp4 protein is 1 of 6 subunits of elongator, a histone acetylase complex that associates with the elongating form of RNA polymerase-2. By database searching with yeast Elp4 as the query, Winkler et al. (2001) obtained cDNAs encoding ELP4 in multiple species, including human. The 424-amino acid human protein is 41% similar to yeast Elp4. Northern blot analysis revealed ubiquitous but variable expression in human tissues.
Kleinjan et al. (2002) identified ELP4, which they called PAXNEB, by sequencing ESTs from a region telomeric of the PAX6 gene (607108). Northern blot analysis detected a 2.0-kb transcript in all cell lines tested. Whole-mount in situ hybridization analysis found wide expression of Paxneb in mouse embryos.
In reporter transgenic mouse embryos, Bhatia et al. (2013) observed expression of an intronic 800-bp Pax6 (607108) cis-regulatory element (SIMO) in early surface ectoderm, lens, diencephalon, and rhomencephalon from embryonic day (E) 9.5, and in the developing retina from E13.5 onward. Eye expression continued through later development and into adulthood, where it was seen in the lens epithelium, retina, and iris. Similar expression patterns were generated by mouse and zebrafish SIMO elements in stable transgenic zebrafish, with strong enhancer activity seen at 48 hours postfertilization (hpf) in the lens in all transgenic fish and more variably in diencephalon and hindbrain. Expression was maintained at 72 hpf.
By genomic sequence analysis, Kleinjan et al. (2002) determined that the PAXNEB gene contains 10 exons transcribed in a telomere-to-centromere direction, opposite to that of PAX6. The PAXNEB gene contains an unusually large last intron covering 134 kb. Promoter analysis indicated a GC-rich region lacking TATA or CAAT boxes, features typical of a housekeeping gene.
Strug et al. (2009) determined that the ELP4 gene contains 12 exons spanning 274 kb. They noted that alternative transcripts have been reported that include or exclude the last 2 exons.
By genomic sequence analysis, Kleinjan et al. (2002) mapped the PAXNEB gene to chromosome 11p13, a region associated with WAGR syndrome (194072) and loss of heterozygosity in breast and bladder cancers.
PAX6 Enhancer Element SIMO
In transgenic zebrafish with deletion of the SIMO element from intron 9 of ELP4, Bhatia et al. (2013) observed complete abolition of Pax6 expression in the lens after 24 hours postfertilization (hpf) despite the continued presence of other defined lens enhancers, demonstrating that the activity of the remote SIMO enhancer element is critically required for continued tissue-specific expression from Pax6 promoters. Pax6-null 'small eye' mouse mutants carrying a SIMO-lacZ transgene showed no staining in the surface ectoderm or lens primordium at E9.5 and E10.5 in contrast to wildtype littermates, indicating that Pax6 is required for activation of the SIMO element. Bhatia et al. (2013) suggested that the SIMO enhancer is not essential in the initial activating phase of PAX6 gene expression but plays a role in maintenance of transcription through a positive-feedback loop.
Aniridia Associated with Cis-Regulatory Element SIMO
In a panel of 60 patients with aniridia (see 617141) without PAX6 (607108) exonic mutations or large-scale chromosomal abnormalities, Bhatia et al. (2013) screened a selection of eye-related cis-regulatory elements and in 1 patient identified a de novo nucleotide variant within an ultraconserved sequence, SIMO, located 150 kb downstream of PAX6 in intron 9 of the ELP4 gene (606985.0001).
Associations Pending Confirmation
For discussion of a possible association between variation in the ELP4 gene and susceptibility to rolandic epilepsy, see 117100.
For discussion of a possible association between copy number variation (CNV) involving the ELP4 gene and susceptibility to neurodevelopmental disorders, including autism, see 616902.
Loss-of-function mutations in the PAX6 gene are associated with the eye anomaly aniridia (106210) in humans and the 'small eye' phenotype in mice. However, some case of aniridia have been identified in which chromosomal rearrangements leave the PAX6 gene intact and interrupt the PAXNEB gene. Using a transgenic mouse model, Kleinjan et al. (2002) failed to show that the small eye phenotype in mice is caused by heterozygous loss of Paxneb function.
Bhatia et al. (2013) generated mice and zebrafish transgenic for mutant versions of SIMO, a PAX6 (607108) cis-regulatory enhancer located within intron 9 of the adjacent ELP4 gene. Transgenic fish lacked signal in the lens but retained expression in other parts of the embryo. In mouse transgenics, expression was lost in the lens but remained in hindbrain and diencephalon; later-stage expression in the retina was also lost. In mouse eyes from embryonic day (E) 14.5, Bhatia et al. (2013) demonstrated that Pax6 efficiently binds to wildtype SIMO-G but not mutant SIMO-T.
In a 17-year-old boy with aniridia (AN2; 617141) who had no PAX6 (607108) exonic mutations or large-scale chromosomal abnormalities, Bhatia et al. (2013) identified heterozygosity for a de novo G-to-T transversion at chr11:31,685,945 (GRCh37) in intron 9 of the ELP4 gene, within an ultraconserved sequence designated SIMO that acts as a strong enhancer in developing ocular structures, located 150 kb downstream of PAX6. Functional analysis demonstrated that the mutation disrupts an autoregulatory PAX6 binding site, causing loss of enhancer activity that results in defective maintenance of PAX6 expression.
Bhatia, S., Bengani, H., Fish, M., Brown, A., Divizia, M. T., de Marco, R., Damante, G., Grainger, R., van Heyningen, V., Kleinjan, D. A. Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. Am. J. Hum. Genet. 93: 1126-1134, 2013. [PubMed: 24290376] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.028]
Kleinjan, D. A., Seawright, A., Elgar, G., van Heyningen, V. Characterization of a novel gene adjacent to PAX6, revealing synteny conservation with functional significance. Mammalian Genome 13: 102-107, 2002. [PubMed: 11889558] [Full Text: https://doi.org/10.1007/s00335-001-3058-y]
Strug, L. J., Clarke, T., Chiang, T., Chien, M., Baskurt, Z., Li, W., Dorfman, R., Bali, B., Wirrell, E., Kugler, S. L., Mandelbaum, D. E., Wolf, S. M., McGoldrick, P., Hardison, H., Novotny, E. J., Ju, J., Greenberg, D. A., Russo, J. J., Pal, D. K. Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to elongator protein complex 4 (ELP4). Europ. J. Hum. Genet. 17: 1171-1181, 2009. [PubMed: 19172991] [Full Text: https://doi.org/10.1038/ejhg.2008.267]
Winkler, G. S., Petrakis, T. G., Ethelberg, S., Tokunaga, M., Erdjument-Bromage, H., Tempst, P., Svejstrup, J. Q. RNA polymerase II Elongator holoenzyme is composed of two discrete subcomplexes. J. Biol. Chem. 276: 32743-32749, 2001. [PubMed: 11435442] [Full Text: https://doi.org/10.1074/jbc.M105303200]