EYA4: Eyes Absent Homolog 4 – A Key Transcriptional Coactivator in Hearing and Organ Development
Comprehensive genomic and clinical overview of EYA4, including its role in sensorineural hearing loss, cardiomyopathy, and cancer.
Gene Information Card
| Symbol | EYA4 |
|---|---|
| Full Name | EYA transcriptional coactivator and phosphatase 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 6q23.2 |
| NCBI Gene ID | 2070 ncbi.nlm.nih.gov/gene/2070 |
| Ensembl ID | ENSG00000112319 |
| UniProt ID | O95677 |
| OMIM ID | 603550 |
| HGNC ID | 3522 |
| Aliases | DFNA10, EYA4, EYA4_HUMAN |
Description
EYA4 (eyes absent homolog 4) is a member of the eyes absent (EYA) family of proteins, which function as transcriptional coactivators and possess intrinsic phosphatase activity. The protein interacts with SIX and DACH family transcription factors to regulate organogenesis, particularly of the inner ear, heart, and kidney. EYA4 is essential for auditory system development and maintenance; heterozygous mutations cause autosomal dominant non-syndromic hearing loss (DFNA10). Additionally, EYA4 variants are associated with dilated cardiomyopathy and have been implicated in several cancers through altered transcriptional programs.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Autosomal dominant non-syndromic hearing loss 10 (DFNA10) | Loss-of-function mutations in EYA4 disrupt transcriptional coactivation of SIX1/DACH targets, impairing cochlear hair cell survival and auditory function. | ClinVar, OMIM #601316 |
| Dilated cardiomyopathy (DCM) | Missense and truncating EYA4 variants reduce phosphatase activity or coactivator function, leading to defective cardiac gene expression and contractile dysfunction. | ClinVar, OMIM #615272 |
| Breast cancer | EYA4 overexpression or aberrant splicing promotes cell proliferation and migration via enhanced SIX1 transcriptional activity and altered DNA repair. | COSMIC, PubMed |
| Ovarian cancer | EYA4 amplification and increased expression correlate with poor prognosis; the phosphatase domain dephosphorylates H2AX to suppress DNA damage signaling. | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Inner ear (cochlea) | — | High |
| Heart | — | Moderate |
| Kidney | — | Moderate |
| Skeletal muscle | — | Low |
| Brain | — | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | — | Moderate expression |
| HeLa | — | Low expression |
| MCF7 | — | Moderate expression |
| K562 | — | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.619C>T (p.Arg207*) | Nonsense | Rare (DFNA10) | Loss of function; premature truncation of coactivator domain |
| c.1129G>A (p.Gly377Arg) | Missense | Rare (DCM) | Impaired phosphatase activity; reduced SIX1 binding |
| c.1489_1490del (p.Leu497fs) | Frameshift | Rare (DFNA10) | Loss of function; truncated protein |
| c.1018A>G (p.Thr340Ala) | Missense | Rare (DCM) | Altered protein stability and coactivator function |
Mutation functional classification
Loss of Function (LOF)
Most EYA4 mutations in DFNA10 and DCM are loss-of-function (nonsense, frameshift, missense) that reduce transcriptional coactivation or phosphatase activity.
Gain of Function (GOF)
Not well documented; some cancer-associated overexpression may act as a gain-of-function by promoting SIX1-driven proliferation.
Dominant Negative (DN)
Truncating mutations may produce dominant-negative isoforms that interfere with wild-type EYA4 or SIX/DACH complex formation.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Retinal determination pathway (EYA-SIX-DACH)
• DNA damage response (H2AX dephosphorylation)
• Organ development (inner ear
• heart
• kidney)
Protein Summary
EYA4 is a 639-amino acid protein (UniProt O95677) containing an N-terminal transactivation domain and a C-terminal EYA domain with tyrosine phosphatase activity. It shuttles between the cytoplasm and nucleus, where it binds SIX and DACH proteins to activate developmental gene expression. The phosphatase domain dephosphorylates histone H2AX (Tyr142) to modulate DNA repair signaling. EYA4 is critical for cochlear hair cell survival and cardiac function; loss-of-function mutations cause hearing loss and cardiomyopathy.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| EYA4 Knockout HEK293 Cell Line | EDJ-KQ4551 | Human | 2070 | Details Get a Quote |
| EYA4 Knockout A-549 Cell Line | EDJ-KQ27186 | Human | 2070 | Details Get a Quote |
| EYA4 Knockout HeLa Cell Line | EDJ-KQ27187 | Human | 2070 | Details Get a Quote |
| EYA4 Knockout HCT 116 Cell Line | EDJ-KQ70131 | Human | 2070 | Details Get a Quote |
