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

Jost Schönberger, Libin Wang, Jordan T. Shin, Do Kim Sang, Frederic F S Depreux, Hao Zhu, Leonard Zon, Anne Pizard, Jae B. Kim, Calum A. MacRae, Andy J. Mungall, J. G. Seidman, Christine E. Seidman

Research output: Contribution to journalArticle

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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 1,2 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.

Original languageEnglish (US)
Pages (from-to)418-422
Number of pages5
JournalNature Genetics
Volume37
Issue number4
DOIs
StatePublished - Apr 2005

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Sensorineural Hearing Loss
Dilated Cardiomyopathy
Mutation
Peptides
Heart Failure
Morpholinos
Antisense Oligonucleotides
Zebrafish
Heart Diseases
Proteins
Embryonic Structures
Hemodynamics
Alleles
Amino Acids
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Schönberger, J., Wang, L., Shin, J. T., Sang, D. K., Depreux, F. F. S., Zhu, H., ... Seidman, C. E. (2005). Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nature Genetics, 37(4), 418-422. https://doi.org/10.1038/ng1527

Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. / Schönberger, Jost; Wang, Libin; Shin, Jordan T.; Sang, Do Kim; Depreux, Frederic F S; Zhu, Hao; Zon, Leonard; Pizard, Anne; Kim, Jae B.; MacRae, Calum A.; Mungall, Andy J.; Seidman, J. G.; Seidman, Christine E.

In: Nature Genetics, Vol. 37, No. 4, 04.2005, p. 418-422.

Research output: Contribution to journalArticle

Schönberger, J, Wang, L, Shin, JT, Sang, DK, Depreux, FFS, Zhu, H, Zon, L, Pizard, A, Kim, JB, MacRae, CA, Mungall, AJ, Seidman, JG & Seidman, CE 2005, 'Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss', Nature Genetics, vol. 37, no. 4, pp. 418-422. https://doi.org/10.1038/ng1527
Schönberger, Jost ; Wang, Libin ; Shin, Jordan T. ; Sang, Do Kim ; Depreux, Frederic F S ; Zhu, Hao ; Zon, Leonard ; Pizard, Anne ; Kim, Jae B. ; MacRae, Calum A. ; Mungall, Andy J. ; Seidman, J. G. ; Seidman, Christine E. / Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. In: Nature Genetics. 2005 ; Vol. 37, No. 4. pp. 418-422.
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