Alternative titles; symbols
HGNC Approved Gene Symbol: EYA4
Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38): 6:133,240,593-133,532,128 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q23.2 | ?Cardiomyopathy, dilated, 1J | 605362 | Autosomal dominant | 3 |
| Deafness, autosomal dominant 10 | 601316 | Autosomal dominant | 3 |
Borsani et al. (1999) presented the detailed characterization of a fourth vertebrate gene, designated EYA4, that is homologous to 'eyes absent' (eya), a key regulator of ocular development in Drosophila. See also EYA1 (601653), EYA2 (601654), and EYA3 (601655). The authors found that EYA4 encodes a 640-amino acid protein containing a highly conserved C-terminal domain of 271 amino acids, which has been designated the eya-homologous region (eya-HR) or eya domain. In Drosophila, eya is known to mediate developmentally important protein-protein interactions. In the developing mouse embryo, Eya4 was expressed primarily in the craniofacial mesenchyme, the dermamyotome, and the limb.
Okabe et al. (2009) found that mouse Eya4, which was originally identified as a cotranscription factor, stimulated expression of Ifnb (147640) and Cxcl10 (147310) in response to the undigested DNA of apoptotic cells. Eya4 enhanced the innate immune response against Newcastle disease virus and vesicular stomatitis virus, and it could associate with the signaling molecules Ips1 (609676), Sting (TMEM173; 612374), and Nlrx1 (611947). Okabe et al. (2009) showed that mouse EYA family members acted as phosphatases for both phosphotyrosine and phosphothreonine. The haloacid dehalogenase domain at the C terminus of Eya4 contained the tyrosine-phosphatase activity, and the N-terminal half carried the threonine-phosphatase activity. Mutations of the threonine-phosphatase, but not the tyrosine-phosphatase, abolished the ability of Eya4 to enhance the innate immune response, suggesting that EYA proteins regulate the innate immune response by modulating the phosphorylation state of signal transducers for intracellular pathogens.
By radiation hybrid analysis and fluorescence in situ hybridization, Borsani et al. (1999) mapped the human EYA4 gene to 6q23. They also detected linkage, with a lod score of greater than 3, to previously mapped reference markers. They genetically mapped the mouse Eya4 gene to chromosome 10 in the vicinity of Aco2 (100850), in a region homologous to human chromosome 6q22-q23.
Autosomal Dominant Deafness 10
In an American and a Belgian family with autosomal dominant nonsyndromic postlingual progressive hearing loss mapping to the DFNA10 locus (601316), Wayne et al. (2001) identified 2 different mutations in the EYA4 gene (603550.0001 and 603550.0002, respectively). Just as EYA proteins interact with members of the SIX (601205) and DACH (603803) protein families during early embryonic development, the authors suggested that EYA4 is also important postdevelopmentally for continued function of the mature organ of Corti.
In a family segregating autosomal dominant nonsyndromic postlingual progressive sensorineural hearing loss (SNHL), Makishima et al. (2007) identified a heterozygous 2-bp insertion (603550.0004) in the EYA4 gene. Noting that the 3 EYA4 mutations reported to date causing nonsyndromic SNHL are predicted to encode truncated EYA proteins with a deleted Eya domain but an intact variable domain, whereas the deletion (603550.0003) causing syndromic hearing loss with DCM partially truncates the variable domain of the protein as well, Makishima et al. (2007) proposed a correlation between EYA4 mutation position and the presence or absence of DCM.
In a 5-generation Australian family with nonsyndromic SNHL, Hildebrand et al. (2007) identified heterozygosity for a splice site mutation (603550.0005) in the EYA4 gene, predicted to cause a frameshift affecting the C-terminal eya-HR domain (residues 369-639).
Dilated Cardiomyopathy with Sensorineural Hearing Loss, Autosomal Dominant
In affected members of a kindred (MCE) with dilated cardiomyopathy (DCM) and heart failure preceded by sensorineural hearing loss mapping to 6q23-q24 (CMD1J; 605362) previously described by Schonberger et al. (2000), Schonberger et al. (2005) identified a large deletion in the EYA4 gene (603550.0003) resulting in a truncated protein that they designated E193. Analysis of biochemical interactions of E193 and of E342 (603550.0001), the shortest mutant protein associated with nonsyndromic hearing loss, revealed that E342 retained partial function, binding wildtype EYA4 and associating with SIX proteins, whereas E193 did not.
To elucidate the role of EYA4 in heart function, Schonberger et al. (2005) studied zebrafish embryos injected with antisense morpholino oligonucleotides and found that attenuated Eya4 transcript levels produced morphologic and hemodynamic features of heart failure.
Depreux et al. (2008) found that Eya4-null mice had severe hearing deficits and developed otitis media with effusion. All 50 mutant mice showed hypervascularity of the tympanic membrane, marked retraction of the tympanic membrane, and middle ear effusions consistent with otitis media. Fifty control mice showed no such abnormalities. Anatomic studies of mutant mice showed an abnormal middle ear cavity and dysmorphology of the eustachian tube. The authors postulated that susceptibility to human otitis media (166760) may involve genetic variation in genes such as EYA4 that regulate middle ear and eustachian tube anatomy.
In affected members of a 5-generation family with autosomal dominant nonsyndromic sensorineural deafness (DFNA10; 601316), Wayne et al. (2001) identified the insertion of 2 adenines at nucleotide 1468 in exon 12 of the EYA4 gene, subsequently generating a frameshift and premature stop codon in exon 14 and eliminating the entire eya-HR. Schonberger et al. (2005) designated the truncated protein E342.
In affected members of a Belgian family with autosomal dominant nonsyndromic sensorineural deafness (DFNA10; 601316), Wayne et al. (2001) identified a C-to-T transition at nucleotide 2200 in exon 20 of the EYA4 gene, generating a premature stop codon that was predicted to eliminate 52 amino acids from the C-terminal eya-homologous region of the protein.
In affected members of a kindred (MCE) with dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (CMD1J; 605362) described by Schonberger et al. (2000), Schonberger et al. (2005) identified a 4,846-bp deletion that encompassed the last nucleotide of exon 9, intron 9, exon 10, and part of intron 10 of the EYA4 gene, resulting in deletion of nucleotides 1022-1245 (corresponding to exons 9 and 10) and a frameshift after residue 193, with 29 new residues and a premature stop codon. The authors designated the mutant protein E193, and noted that it was 143 residues shorter than the shortest nonsyndromic-SNHL-associated EYA4 peptide identified to date (E342; 603550.0001) and affected both the eya-HR and the variable region of the protein. The deletion was absent from 300 control chromosomes.
In affected members of a family segregating autosomal dominant nonsyndromic postlingual progressive sensorineural hearing loss (DFNA10; 601316), Makishima et al. (2007) identified heterozygosity for a 2-bp insertion (1490insAA) in exon 12 of the EYA4 gene, predicted to result in a truncated EYA4 protein with an intact variable domain and a deleted Eya domain. The mutation was not found in unaffected family members or in 96 ethnically matched control DNA samples.
In affected members of a 5-generation Australian family with nonsyndromic sensorineural hearing loss (DFNA10; 601316), Hildebrand et al. (2007) identified heterozygosity for a variation within a polypyrimidine tract, 1282-12T-A, in intron 14 of the EYA4 gene that introduces a new 3-prime splice acceptor site, predicted to cause aberrant splicing of EYA4 pre-mRNA and a frameshift involving the C-terminal eya-HR domain (residues 369-639). The mutation was not found in 150 control samples.
Borsani, G., DeGrandi, A., Ballabio, A., Bulfone, A., Bernard, L., Banfi, S., Gattuso, C., Mariani, M., Dixon, M., Donnai, D., Metcalfe, K., Winter, R., Robertson, M., Axton, R., Brown, A., van Heyningen, V., Hanson, I. EYA4, a novel vertebrate gene related to Drosophila eyes absent. Hum. Molec. Genet. 8: 11-23, 1999. [PubMed: 9887327] [Full Text: https://doi.org/10.1093/hmg/8.1.11]
Depreux, F. F. S., Darrow, K., Conner, D. A., Eavey, R. D., Liberman, M. C., Seidman, C. E., Seidman, J. G. Eya4-deficient mice are a model for heritable otitis media. J. Clin. Invest. 118: 651-658, 2008. [PubMed: 18219393] [Full Text: https://doi.org/10.1172/JCI32899]
Hildebrand, M. S., Coman, D., Yang, T., Gardner, R. J. M., Rose, E., Smith, R. J. H., Bahlo, M., Dahl, H.-H. M. A novel splice site mutation in EYA4 causes DFNA10 hearing loss. Am. J. Med. Genet. 143A: 1599-1604, 2007. Note: Erratum: Am. J. Med. Genet. 146A: 1099 only, 2008. [PubMed: 17568404] [Full Text: https://doi.org/10.1002/ajmg.a.31860]
Makishima, T., Madeo, A. C., Brewer, C. C., Zalewski, C. K., Butman, J. A., Sachdev, V., Arai, A. E., Holbrook, B. M., Rosing, D. R., Griffith, A. J. Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain. Am. J. Med. Genet. 143A: 1592-1598, 2007. [PubMed: 17567890] [Full Text: https://doi.org/10.1002/ajmg.a.31793]
Okabe, Y., Sano, T., Nagata, S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460: 520-524, 2009. [PubMed: 19561593] [Full Text: https://doi.org/10.1038/nature08138]
Schonberger, J., Levy, H., Grunig, E., Sangwatanaroj, S., Fatkin, D., MacRae, C., Stacker, H., Halpin, C., Eavey, R., Philbin, E. F., Katus, H., Seidman, J. G., Seidman, C. E. Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24. Circulation 101: 1812-1818, 2000. [PubMed: 10769282] [Full Text: https://doi.org/10.1161/01.cir.101.15.1812]
Schonberger, J., Wang, L., Shin, J. T., Kim, S. D., Depreux, F. F. S., Zhu, H., Zon, L., Pizard, A., Kim, J. B., MacRae, C. A., Mungall, A. J., Seidman, J. G., Seidman, C. E. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nature Genet. 37: 418-422, 2005. [PubMed: 15735644] [Full Text: https://doi.org/10.1038/ng1527]
Wayne, S., Robertson, N. G., DeClau, F., Chen, N., Verhoeven, K., Prasad, S., Tranebjarg, L., Morton, C. C., Ryan, A. F., Van Camp, G., Smith, R. J. H. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum. Molec. Genet. 10: 195-200, 2001. [PubMed: 11159937] [Full Text: https://doi.org/10.1093/hmg/10.3.195]