PUBLICATION
Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss
- Authors
- Schonberger, J., Wang, L., Shin, J.T., Kim, S.D., Depreux, F.F., Zhu, H., Zon, L., Pizard, A., Kim, J.B., MacRae, C.A., Mungall, A.J., Seidman, J.G., and Seidman, C.E.
- ID
- ZDB-PUB-050301-6
- Date
- 2005
- Source
- Nature Genetics 37(4): 418-422 (Journal)
- Registered Authors
- MacRae, Calum A., Shin, Jordan, Zon, Leonard I.
- Keywords
- none
- MeSH Terms
-
- Animals
- Blotting, Northern
- Cardiomyopathy, Dilated/genetics*
- Embryo, Nonmammalian/cytology
- Embryo, Nonmammalian/metabolism
- Exons/genetics
- Eye Proteins/genetics
- Hearing Loss, Sensorineural/genetics*
- Heart/physiopathology
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Immunoprecipitation
- In Situ Hybridization
- Mice
- Mutation/genetics*
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Oligonucleotides, Antisense/pharmacology
- Peptide Fragments/genetics
- Peptide Fragments/metabolism
- Trans-Activators/genetics*
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zebrafish/embryology
- Zebrafish/metabolism*
- PubMed
- 15735644 Full text @ Nat. Genet.
Citation
Schonberger, J., Wang, L., Shin, J.T., Kim, S.D., Depreux, F.F., Zhu, H., Zon, L., Pizard, A., Kim, J.B., MacRae, C.A., Mungall, A.J., Seidman, J.G., and Seidman, C.E. (2005) Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nature Genetics. 37(4):418-422.
Abstract
We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping