A 4bp-Insertion in the eya-Homologous Region (eyaHR) of EYA4 Causes Hearing Impairment in a Hungarian Family Linked to DFNA10

Abstract

Background: Hereditary hearing impairment (HHI) is a heterogeneous class of disorders that shows various patterns of inheritance and involves a multitude of different genes. Mutations in the EYA4 gene are responsible for postlingual, progressive, autosomal dominant hearing loss at the DFNA10 locus. EYA4 is orthologous to the Drosophila gene eya ("eyes absent"), a key regulator of eye formation. EYA4 plays an important role in several developmental processes. Material and Methods: Here we report a Hungarian family displaying sensorineural, progressive hearing impairment. The family comprising four generations with 11 affected and 8 unaffected members was subjected to genome-wide linkage analysis and candidate gene sequencing.Results: By linkage analysis, the chromosomal region 6q22.3 was shown to segregate with the disease. Mutation analysis of the EYA4 gene, which maps to 6q22.3, revealed an insertion of 4 bp (1558insTTTG) in all affected family members. This insertion creates a frameshift and results in a stop codon at position 379. Hence, nearly the complete "eya homologous region" (eyaHR), which is essential for the protein function, would be deleted in the mutant EYA4 protein if the transcription were found to be stable. Conclusions: This family is the third one linked to DFNA10 and revealing a mutation in the EYA4 gene. In all three families, the mutations are localized in different regions of the eyaHR, suggesting that this protein contains several functional subregions with different tissue-specific importance.

Eya4-deficient mice are a model for heritable otitis media

“…Human EYA1 mutations cause branchiootorenal (BOR) syndrome (OMIM 113650) (8), with branchial arch defects including lacrimal duct abnormalities, preauricular fistulae, and hearing loss (mixed conductive and sensorineural), with abnormally shaped external ears, cochlear malformations, and renal anomalies (9). EYA4 mutations cause sensorineural hearing loss (DFNA10 locus on chromosome 6) without affecting external ear or other craniofacial structures; these mutations are sometimes accompanied by cardiomyopathy (10)(11)(12)(13). The onset of hearing loss due to EYA4 mutations is notably broad, ranging from early in childhood to adulthood (14), and hearing deficits are not stable until adulthood.…”

Eya4 regulation of Na+/K+-ATPase is required for sensory system development in zebrafish

“…Interactions with Six proteins permit Eya proteins to translocate into the nucleus (Hanson, 2001;Rebay et al, 2005) where phosphatase activity releases transcriptional repression caused by Six-Dachshund and other molecules (Li et al, 2003;Rayapureddi et al, 2003;Tootle et al, 2003). Human deletions in EYA4 cause a dominant form of sensorineural hearing loss (Pfister et al, 2002;Wayne et al, 2001), which sometimes is accompanied by late-onset dilated cardiomyopathy (Schonberger et al, 2000;Schonberger et al, 2005). The gene targets regulated by Eya4, Six and Dachshund in the ear or heart are unknown.…”

Frequent Methylation ofEyes Absent 4Gene in Barrett's Esophagus and Esophageal Adenocarcinoma

“…Eyes absent works as a key regulator of ocular differentiation and may modulate apoptosis (15,16). In humans, inherited mutations in EYA genes have been associated with syndromatic developmental abnormalities (18)(19)(20)(21)(22). A potential role of EYA4 gene in human cancer was recently suggested by a microarray-based methylation analysis that showed EYA4 is frequently methylated in colorectal cancer but not methylated in normal mucosa (23).…”