Eya4-deficient mice are a model for heritable otitis media

Depreux, Frederic; Darrow, Keith N.; Conner, David A.; Eavey, Roland D.; Liberman, M. Charles; Seidman, Christine E.; Seidman, J. G.

doi:10.1172/jci32899

Cited by 63 publications

(79 citation statements)

References 45 publications

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“…Unfortunately, data to support this possibility have yet to be reported. As reported in this issue of the JCI, Depreux et al (6), in the process of investigating hearing loss in Eya4 -/-mice, found that these mutant animals had OME. The existence of a genetic basis for OME has been previously suggested, as the incidence of OME has been shown to be higher in twin siblings (3); but in their current study Depreux et al propose that deletion of a specific gene, Eya4, causes OME (6).…”

Section: A Genetic Basis For Omementioning

confidence: 83%

“…The study by Depreux et al (6) shows that the Eya4 gene may play a critical role in structuring the ET and that immature development of these structures predisposes Eya4 -/-mice to OME. While the degree of conductive hearing loss in the Eya4 -/-mouse is unknown, and may be overshadowed by inner-ear defects, the degree of similarity between the OME dysmorphology of the middle ear observed in the mutant mouse and that observed in humans is nevertheless remarkable.…”

Section: A Genetic Basis For Omementioning

confidence: 99%

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Can you hear me now? A genetic model of otitis media with effusion

Lazaridis

Saunders²

2008

J. Clin. Invest.

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Otitis media with effusion (OME) is characterized by the occurrence of fluid in the middle-ear cavity in the absence of any signs of acute ear infection and occurs most frequently in children with auditory or eustachian tube dysfunction. Its chronic form is an important clinical issue for pediatricians and otologists alike. The study by Depreux et al. in this issue of the JCI shows that absence of the transcriptional activator Eya4 in knockout mice results in abnormal structuring of the eustachian tube, thus predisposing these animals to OME (see the related article beginning on page 651). The development of this genetics-based animal model is an important advance for understanding OME and for exploring new avenues of treatment.Nonstandard abbreviations used: ET, eustachian tube; Eya4, eyes absent 4 homolog; OME, otitis media with effusion.

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Section: A Genetic Basis For Omementioning

confidence: 83%

Section: A Genetic Basis For Omementioning

confidence: 99%

Can you hear me now? A genetic model of otitis media with effusion

Lazaridis

Saunders²

2008

J. Clin. Invest.

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“…Moreover, since EYA4 is reported to form homodimers (Schönberger et al, 2005), truncated proteins may have a dominant negative effect on the full-length EYA4. Recently, Eya4-deficient mice have been reported to exhibit abnormal middle ear cavities and Eustachian tube dysmorphology (Depreux et al, 2008). However, fine structural abnormalities of the cerebrum have not been investigated.…”

Section: E953 Discussionmentioning

confidence: 99%

EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts withSIX3both physically and functionally

et al. 2009

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Holoprosencephaly (HPE) is the most common congenital malformation of the developing human forebrain, in which the two cerebral hemispheres fail to separate to various degrees. Although pathological mutations have been identified in up to nine genes, a number of other genes as well as environmental factors are likely to be involved in HPE. Here, we describe a case with the middle interhemispheric variant, a milder variant of HPE, carrying a deletion of ~10.4 Mb at 6q22.31-q23.2, which includes the EYA4 gene. EYA4 is one of four vertebrate orthologs of the Drosophila melanogaster gene, eyes absent. EYA4 was co-immunoprecipitated with SIX3, the product of one of the known HPE genes. Moreover, the EYA4 protein was observed to be recruited to the nucleus by the nuclear protein SIX3 under a confocal microscope. EYA4 is a transcriptional coactivator, and was shown to cooperate with transcription factor SIX3 by reporter gene assays. These results demonstrate physical and functional association between EYA4 and SIX3, suggesting that EYA4 is a novel candidate gene of HPE, whose haploinsufficiency leads to HPE through the compromised function of SIX3.

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“…There are multiple factors involved in this process. It has been reported that anatomic abnormality, genetic predisposition, and middle ear immunity play important roles in the pathogenesis of COM [3][4][5][6][7]. To make middle ear infection chronic, there must be some compromised innate or adaptive immunity in the middle ear mucosa.…”

Section: Introductionmentioning

confidence: 99%