Alternative titles; symbols
HGNC Approved Gene Symbol: EYA3
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:27,970,344-28,088,610 (from NCBI)
Abdelhak et al. (1997) identified 3 members of a novel family homologous to Drosophila 'eyes absent' gene (eya). One of these, EYA1 (601653), was demonstrated to be mutant in cases of branchiootorenal dysplasia (BOR; 113650). EYA2 (601654) and EYA3, like EYA1, are expressed in the ninth week of human development and may also underlie developmental defects.
Zimmerman et al. (1997) mapped the murine Eya3 gene to mouse chromosome 4 in the region syntenic with human 1p36. In the mouse, no recombination was detected between the Eya3 gene and the gene encoding the oncogene FGR (164940) which in human is located on 1p36.2-p36.1. By fluorescence in situ hybridization, Zimmerman et al. (1997) established that the human EYA3 gene is on 1p36.
Stumpf (2022) mapped the EYA3 gene to chromosome 1p35.3 based on an alignment of the EYA3 sequence (GenBank BC029500) with the genomic sequence (GRCh38).
Xu et al. (1997) showed that in the limbs of 10.5-day mouse embryos, Eya1 expression was largely restricted to the flexor tendons, whereas Eya2 was expressed in the extensor tendons and probably also in the ligaments of the phalanges. They demonstrated that the proline/serine/threonine-rich N-terminal regions of the protein products of the Eya1, Eya2, and Eya3 genes have transcriptional activator activity. These results supported a role for the Eya genes in connective tissue patterning in the limbs.
For discussion of a possible association between hemifacial microsomia (see 164210) and variation in the EYA3 gene, see 601655.0001.
Tingaud-Sequeira et al. (2021) used an antisense morpholino to knock down eya3 in zebrafish, and observed microphthalmia/anophthalmia in 80% of embryos at 48 hours postfertilization; a curved-tail phenotype was also present in 50% of embryos, corresponding to those with the most marked eye changes. All embryos with both eye and tail changes died before 5 days postfertilization, and the surviving embryos showed alterations of the normal craniofacial architecture. Wildtype human EYA3 cRNA partially rescued the altered phenotypes.
This variant is classified as a variant of unknown significance because its contribution to craniofacial microsomia (see 164210) has not been confirmed.
Tingaud-Sequeira et al. (2021) reported 2 brothers from a New Zealand family with craniofacial anomalies. One brother had hemifacial microsomia, asymmetric bilateral microtia, cleft palate, pectus carinatum, and psychomotor delay. The other brother had asymmetric bilateral ear anomalies, including right anotia, left microtia, and preauricular tags, and also showed pectus carinatum, cleft palate, and tracheomalacia. Whole-exome sequencing in the 2 brothers identified heterozygosity for a c.1073A-G transition (c.1073A-G, NM_001282561.1) in the EYA3 gene, resulting in an asn358-to-ser (N358S) substitution at a highly conserved residue. The mutation was inherited from their unaffected mother and was also found in an unaffected older brother; the older brother's son and the maternal grandfather both exhibited sinus pits, but neither was available for DNA analysis. The authors suggested that the segregation in this family represented incomplete penetrance and variable expressivity. Screening of EYA3 in 122 additional patients with oculoauriculovertebral spectrum (OAVS) identified a French girl who was heterozygous for the same N358S mutation. She had bilateral ear anomalies, including ear dysplasia, preauricular tags, and sinus pits; ocular anomalies, including epibulbar dermoid and glaucoma; and thoracic hemivertebrae at T11 and T12. In addition she had microretrognathia and glossoptosis, and died at age 2 years due to glossoptosis. She inherited the N358S variant from her unaffected father, whose maternal uncle had preauricular tags. Functional analysis in transfected HeLa cells showed an increased half-life of the mutant compared to wildtype EYA3, without impact on its ability to dephosphorylate H2AFX after DNA repair pathway induction. The authors stated that the identification of a recurrent missense variant in 2 independent families supports EYA3 as a strong candidate gene for craniofacial microsomia.
Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., Francis, M., Lacombe, D., Vigneron, J., Charachon, R., Boven, K., Bedbeder, P., Van Regemorter, N., Weissenbach, J., Petit, C. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nature Genet. 15: 157-164, 1997. [PubMed: 9020840] [Full Text: https://doi.org/10.1038/ng0297-157]
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/04/2022.
Tingaud-Sequeira, A., Trimouille, A., Salaria, M., Stapleton, R., Claverol, S., Plaisant, C., Bonneu, M., Lopez, E., Arveiler, B., Lacombe, D., Rooryck, C. A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum. Hum. Genet. 140: 933-944, 2021. [PubMed: 33475861] [Full Text: https://doi.org/10.1007/s00439-021-02255-6]
Xu, P.-X., Cheng, J., Epstein, J. A., Maas, R. L. Mouse Eya genes are expressed during limb tendon development and encode a transcriptional activation function. Proc. Nat. Acad. Sci. 94: 11974-11979, 1997. [PubMed: 9342347] [Full Text: https://doi.org/10.1073/pnas.94.22.11974]
Zimmerman, J. E., Bui, Q. T., Steingrimsson, E., Nagle, D. L., Fu, W., Genin, A., Spinner, N. B., Copeland, N. G., Jenkins, N. A., Bucan, M., Bonini, N. M. Cloning and characterization of two vertebrate homologs of the Drosophila eyes absent gene. Genome Res. 7: 128-141, 1997. [PubMed: 9049631] [Full Text: https://doi.org/10.1101/gr.7.2.128]