Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss

Schönberger, Jost; Wang, Libin; Shin, Jordan T.; Kim, Sang Do; Depreux, Frederic; Zhu, Min; Zon, Leonard I.; Pizard, Anne; Kim, Jae Bum; MacRae, Calum A.; Mungall, Andrew J.; Seidman, Jonathan G.

doi:10.1038/ng1527

Cited by 185 publications

(172 citation statements)

References 16 publications

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“…In contrast, patients with CMD1J or DFNA10 carry mutations that produce either a frameshift or a stop codon resulting in the translation of truncated proteins deficient in the C-terminal EYA domain to various degrees. Although EYA4 proteins lacking the EYA domain are not able to associate with SIX family proteins, demonstrated herein and by others (Schönberger et al, 2005), these truncated proteins may still have compromised functions. 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.…”

Section: E953 Discussionsupporting

confidence: 49%

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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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Section: E953 Discussionsupporting

confidence: 49%

“…Mutations of EYA4 have been reported to cause sensorineural hearing loss (SNHL) with or without dilated cardiomyopathy (DCM) (CMD1J; MIM# 605362 and DFNA10; MIM# 601316, respectively) (Wayne et al, 2001;Schönberger et al, 2005), which are distinct from MIH. In the present case, the subject did not exhibit any signs of SNHL or DCM.…”

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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“…Eya3/4 are expressed in the head mesenchyme, and elevated levels of transcripts were found in anterior brain regions but were excluded from cranial placodes. Mutations in Eya4 have been reported as the causative gene of hearing impairment in humans and causes dilated cardiomyopathy in zebrafish (Wayne et al, 2001;Schonberger et al, 2005). The overall structure of EYA proteins is highly conserved.…”

Section: Introductionmentioning

confidence: 99%

Xeya3 regulates survival and proliferation of neural progenitor cells within the anterior neural plate of Xenopus embryos

Kriebel¹,

Müller²,

Hollemann³

2007

Developmental Dynamics

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“…Six family homeodomain genes and eyes absent genes have been implicated in mammalian apoptosis and various human diseases, including cancer (35,36), cardiomyopathy (37), and developmental disorders (38)(39)(40). Mutations in SIX3 were identified in human patients with holoprosencephaly (HPE), a severe malformation of the forebrain characterized by an incomplete segregation of the cerebral hemispheres (38).…”

Section: Human Diseases Caused By Mutations In Six Family Homeodomainmentioning

confidence: 99%

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only geneegl-1inCaenorhabditis elegans

Hirose

Galvin

Horvitz

2010

Proc. Natl. Acad. Sci. U.S.A.

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The decision of a cell to undergo programmed cell death is tightly regulated during animal development and tissue homeostasis. Here, we show that the Caenorhabditis elegans Six family homeodomain protein C. elegans homeobox (CEH-34) and the Eyes absent ortholog EYA-1 promote the programmed cell death of a specific pharyngeal neuron, the sister of the M4 motor neuron. Loss of either ceh-34 or eya-1 function causes survival of the M4 sister cell, which normally undergoes programmed cell death. CEH-34 physically interacts with the conserved EYA domain of EYA-1 in vitro. We identify an egl-1 5′ cis-regulatory element that controls the programmed cell death of the M4 sister cell and show that CEH-34 binds directly to this site. Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. We conclude that an evolutionarily conserved complex that includes CEH-34 and EYA-1 directly activates egl-1 expression through a 5′ cis-regulatory element to promote the programmed cell death of the M4 sister cell. We suggest that the regulation of apoptosis by Six and Eya family members is conserved in mammals and involved in human diseases caused by mutations in Six and Eya.cell death | sine oculis | eyes absent | transcription A poptosis, also referred to as programmed cell death, plays fundamental roles in animal development and tissue homeostasis (1). The misregulation of apoptosis is associated with many human disorders, including cancer and neurodegenerative and autoimmune diseases (2). Determining how particular cells are specified to live or die is critical to understanding both normal animal development and human diseases associated with the misregulation of apoptotic cell death.During the development of the Caenorhabditis elegans hermaphrodite, 131 somatic cells undergo programmed cell death (3,4). Genetic studies of programmed cell death in C. elegans have defined an evolutionarily conserved pathway that executes this process (5). This pathway consists of four genes, egl-1 [egg-laying defective (egl)], ced-9 [cell-death abnormal (ced)], ced-4, and ced-3, all of which are conserved from C. elegans to mammals. Although much is understood about the pathway responsible for the execution of programmed cell death in both C. elegans and other animals, less is known about the mechanisms that control how specific cells decide whether to survive or die by programmed cell death. In C. elegans, most of the genes identified to control cell-death specification encode transcription factors, some of which are known to directly regulate the transcription of cell-death genes (6-11). For example, the Snail family transcription factor CES-1 [cell-death specification (ces)] can directly repress expression of the BH3-only proapoptotic gene egl-1 and prevent the deaths of the NSM sister cells (6, 7). This regulatory mechanism is conserved in mammals and has been implicated in human cancer: acute lymphoblastic leukemia results from an overexpression of the CES-1 homolog Slug, which directly represses expre...

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Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss

Cited by 185 publications

References 16 publications

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

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

Xeya3 regulates survival and proliferation of neural progenitor cells within the anterior neural plate of Xenopus embryos

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only geneegl-1inCaenorhabditis elegans

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