Alternative titles; symbols
HGNC Approved Gene Symbol: IRF2BPL
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:77,024,543-77,028,708 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures | 618088 | Autosomal dominant | 3 |
The IRF2BPL gene encodes a protein that is expressed in many organs, including the central nervous system. Evidence suggests that it acts as a transcriptional activator and may also function as an E3 ubiquitin ligase (summary by Marcogliese et al., 2018).
By positional cloning and database analysis, Rampazzo et al. (2000) identified C14ORF4. The deduced 796-amino acid protein has a calculated molecular mass of 82.7 kD. It is proline-rich and contains N-terminal polyglutamine and polyalanine tracts, a C-terminal C3HC4-type ring finger domain, and 2 putative transmembrane domains. It also has a potential nuclear targeting signal, an endoplasmic reticulum retention signal, 3 possible PEST sequences, and putative sites for phosphorylation, N-glycosylation, and amidation. The size of the polyglutamine tract varied from 20 to 31 CAG repeats in 50 unrelated normal Italian individuals examined. RT-PCR analysis of human tissues detected strong expression in heart, moderate expression in skeletal muscle and pancreas, and weak expression in brain, kidney, liver, testis, thyroid, and lymphocytes.
Rampazzo et al. (2000) determined that the C14ORF4 gene is intronless. The 5-prime flanking region contains no TATA or CAATT boxes, but it is high in GC content and includes 2 SP1 (189906)-binding sites. The 3-prime end contains 2 polyadenylation signals.
By genomic sequence analysis and radiation hybrid mapping, Rampazzo et al. (2000) mapped the C14ORF4 gene to chromosome 14q24.3.
Using DNA microarrays, Heger et al. (2007) found that expression of C14orf4, which they termed Eap1, increased in the medial basal hypothalamus, but not cerebral cortex, of female rhesus monkeys at early puberty and increased further at midpuberty. Female mice underwent a similar increase of Eap1 expression in hypothalamus, but not cortex, during puberty. In situ hybridization showed that Eap1 mRNA was abundant in cells of hypothalamic nuclei involved in Gnrh (152760) secretion, such as the arcuate nucleus. Immunohistochemical analysis localized Eap1 to cell nuclei. Inhibition of Eap1 by RNAi targeted to the preoptic area of female rats disrupted the estrous cycle and reduced plasma gonadotropin levels, suggesting altered Gnrh release. These abnormalities were accompanied by stunted antral follicular development and formation of ovarian cysts. Heger et al. (2007) noted that EAP1 is located in a region of chromosome 14 affected by maternal uniparental disomy 14 (608149), and they proposed that EAP1 may be 1 of the genes affected in this syndrome.
Using immunoprecipitation mass spectrometry analysis, Yokoyama et al. (2021) identified EAP1 as a coregulator associated with androgen receptor (AR; 313700) in LNCaP human prostate cancer cells. Immunofluorescence analysis revealed colocalization of EAP1 with AR in the nucleus of LNCaP cells. EAP1 functioned as an E3 ubiquitin ligase for AR and HDAC1 (601241), suggesting that EAP1 enhances AR transcriptional activity by regulating AR-HDAC1 complex levels via ubiquitin-proteasome pathways. Immunohistochemical analysis in human prostate tumor tissue showed overexpression of EAP1 that correlated with poor outcome.
In 7 unrelated patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified heterozygous mutations in the IRF2BPL gene (see, e.g., 611720.0001-611720.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing. The mutations occurred de novo in all patients from whom parental DNA was available for analysis. Five patients carried nonsense mutations, whereas 2 patients with a slightly less severe phenotype carried missense mutations. Overexpression of nonsense mutations in Drosophila failed to induce lethality, as was observed with overexpression of the wildtype gene, suggesting that the nonsense mutations resulted in a loss of function. Expression of the K418N mutation (611720.0005) resulted in lethality at higher temperatures, suggesting that it causes a partial loss of function, whereas expression of the P372R variant (611720.0004) resulted in lethality, similar to wildtype. Partial knockdown of the pits gene in Drosophila using RNAi resulted in progressive neurologic motor and learning dysfunction, and specific knockdown of the gene in photoreceptors of the eye caused progressive abnormalities. Complete disruption of the pits gene was toxic to the fly, resulting in lethality, as was overexpression of both pits and IRF2BPL. The findings suggested that the IRF2BPL gene is involved in both neurologic development and neuronal maintenance.
Using exome sequencing, Tran Mau-Them et al. (2019) identified different de novo heterozygous nonsense or frameshift mutations in the IRF2BPL gene (see, e.g., 611720.0006 and 611720.0007) in 11 unrelated patients with NEDAMSS. All of the mutations were absent from the gnomAD database and were expected to encode a protein lacking the C-terminal RING-finger domain. RNA analyses on patient-derived fibroblasts were consistent with nonsense-mediated decay escape, suggesting that the shortened proteins might be translated.
Li and Li (2017) found that suppression of Eap1 in rat hypothalamus via intracerebroventricular injection delayed vaginal opening and perturbed ovary development. Further analysis showed that Eap1 regulated puberty in rats through Gnrh (GNRH1; 152760), without affecting the Gnrh secretion regulator Kiss1 (603286).
Marcogliese et al. (2018) found that the closest ortholog to the IRF2BPL gene in Drosophila, called 'pits,' was broadly detected, including in the nervous system. Expression was detected in various regions of the brain, including in the mushroom body and in the nuclei, cell bodies, and axons of neurons. Disruption of the pits gene was toxic to the fly, resulting in lethality, as was overexpression of both pits and IRF2BPL. The pits gene is located on the X chromosome in Drosophila.
In 2 unrelated patients (patients 2 and 3) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified a heterozygous c.562C-T transition (c.562C-T, NM_024496.3) in the IRF2BPL gene, resulting in an arg188-to-ter (R188X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. The mutation was confirmed to occur de novo in 1 patient; parental DNA was not available for the other patient.
In a 16-year-old girl (patient 4) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified a de novo heterozygous c.379C-T transition (c.379C-T, NM_024496.3) in the IRF2BPL gene, resulting in a gln127-to-ter (Q127X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In a 43-year-old man (patient 5) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified a de novo heterozygous c.376C-T transition (c.376C-T, NM_024496.3) in the IRF2BPL gene, resulting in a gln126-to-ter (Q126X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In an 11-year-old boy (patient 6) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified a de novo heterozygous c.1115C-G transversion (c.1115C-G, NM_024496.3) in the IRF2BPL gene, resulting in a pro372-to-arg (P372R) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In a 2.5-year-old girl (patient 7) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Marcogliese et al. (2018) identified a de novo heterozygous c.1254G-C transversion (c.1254G-C, NM_024496.3) in the IRF2BPL gene, resulting in a lys418-to-asn (K418N) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In a 10.5-year-old girl (patient 7) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Tran Mau-Them et al. (2019) identified a de novo heterozygous 1-bp deletion (c.962delC, NM_024496.3) in the IRF2BPL gene, resulting in a frameshift and a premature termination codon (Ala321GlufsTer24). The mutation was found by exome sequencing and was not present in the gnomAD database.
In a 5-year-old boy (patient 9) with neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS; 618088), Tran Mau-Them et al. (2019) identified a de novo heterozygous 2-bp deletion (c.2135_2136delGT) in the IRF2BPL gene, resulting in a frameshift and a premature termination codon (Leu713SerfsTer56). The mutation was found by exome sequencing and was not present in the gnomAD database.
Heger, S., Mastronardi, C., Dissen, G. A., Lomniczi, A., Cabrera, R., Roth, C. L., Jung, H., Galimi, F., Sippell, W., Ojeda, S. R. Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis. J. Clin. Invest. 117: 2145-2154, 2007. [PubMed: 17627301] [Full Text: https://doi.org/10.1172/JCI31752]
Li, C., Li, P. Enhanced at puberty-1 (Eap1) expression critically regulates the onset of puberty independent of hypothalamic Kiss1 expression. Cell. Physiol. Biochem. 43: 1402-1412, 2017. [PubMed: 29017168] [Full Text: https://doi.org/10.1159/000481872]
Marcogliese, P. C., Shashi, V., Spillmann, R. C., Stong, N., Rosenfeld, J. A., Koenig, M. K., Martinez-Agosto, J. A., Herzog, M., Chen, A. H., Dickson, P. I., Lin, H. J., Vera, M. U., and 22 others. IRF2BPL is associated with neurological phenotypes. Am. J. Hum. Genet. 103: 245-260, 2018. Note: Erratum: Am. J. Hum. Genet. 103: 456 only, 2018. [PubMed: 30057031] [Full Text: https://doi.org/10.1016/j.ajhg.2018.07.006]
Rampazzo, A., Pivotto, F., Occhi, G., Tiso, N., Bortoluzzi, S., Rowen, L., Hood, L., Nava, A., Danieli, G. A. Characterization of C14orf4, a novel intronless human gene containing a polyglutamine repeat, mapped to the ARVD1 critical region. Biochem. Biophys. Res. Commun. 278: 766-774, 2000. [PubMed: 11095982] [Full Text: https://doi.org/10.1006/bbrc.2000.3883]
Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., and 26 others. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy. Genet. Med. 21: 1008-1014, 2019. [PubMed: 30166628] [Full Text: https://doi.org/10.1038/s41436-018-0143-0]
Yokoyama, A., Kouketsu, T., Otsubo, Y., Noro, E., Sawatsubashi, S., Shima, I., Satoh, I., Kawamura, S., Suzuki, T., Igarashi, K., Sugawara, A. Identification and functional characterization of a novel androgen receptor coregulator, EAP1. J. Endocr. Soc. 5: bvab150, 2021. [PubMed: 34585037] [Full Text: https://doi.org/10.1210/jendso/bvab150]