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 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.
Schönberger
Jost
J
Harvard Medical School, Department of Genetics, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Wang
Libin
L
Shin
Jordan T
JT
Kim
Sang Do
SD
Depreux
Frederic F S
FF
Zhu
Hao
H
Zon
Leonard
L
Pizard
Anne
A
Kim
Jae B
JB
Macrae
Calum A
CA
Mungall
Andy J
AJ
Seidman
J G
JG
Seidman
Christine E
CE
D000818:Animals; D015152:Blotting, Northern; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006321:Heart / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D015534:Trans-Activators; D014157:Transcription Factors; D000097607:Homeobox Protein SIX3; C117736:EYA4 protein, human; C490947:Six1 protein, mouse; C497420:Six2 protein, mouse