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


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 alleles1,2 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.

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We thank the members of families MCE and MDB, without whose assistance this study would not have been possible, and H. Levy, B. Bruneau, B. McDonough, C. Duffy, J. Rivera-Feliciano, J.L. Galloway, D. Fatkin, H. Stäcker, R. Eavey, C. Halpin, D. Fox, V. VanderLaan and the Westshore Cardiology Group for helpful comments, technical expertise and support. This work was supported by grants from the Howard Hughes Medical Institutes (J.S., L.W., J.G.S. and C.E.S.), the National Institutes of Health (J.G.S. and C.E.S.), the German Research council (J.S.) and the Bugher foundation (J.S. and J.G.S.).

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Correspondence to Christine E Seidman.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Comparison of Eya4 protein sequences in zebrafish, mouse, and human. (PDF 75 kb)

Supplementary Fig. 2

Additional whole mount in situ hybridization of zebrafish Eya4 during embryogenesis. (PDF 10841 kb)

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Figure 1: Structure of the mutated EYA4 allele encoding E193.
Figure 2: Zebrafish eya4 is expressed in the heart.
Figure 3: Cardiac pathology in zebrafish embryos injected with morpholinos against eya4.
Figure 4: Blood cell circulation velocities observed in one contraction cycle from zebrafish embryos.
Figure 5: Protein interactions between Eya4 proteins and Six transcription factors.