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

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.

• Authors: Jost Schönberger, Libin Wang, Jordan T Shin, Sang Do Kim, 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
• Journal: Nature genetics (Nat Genet) Vol. 37 Issue 4 Pg. 418-22 (Apr 2005) ISSN: 1061-4036 [Print] United States
• PMID: 15735644 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• EYA4 protein, human
• Eye Proteins
• Homeodomain Proteins
• Nerve Tissue Proteins
• Oligonucleotides, Antisense
• Peptide Fragments
• Sine oculis homeobox homolog 3 protein
• Six1 protein, mouse
• Six2 protein, mouse
• Trans-Activators
• Transcription Factors

Topics

• Animals
• Blotting, Northern
• Cardiomyopathy, Dilated (genetics)
• Embryo, Nonmammalian (cytology, metabolism)
• Exons (genetics)
• Eye Proteins (genetics)
• Hearing Loss, Sensorineural (genetics)
• Heart (physiopathology)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Immunoprecipitation
• In Situ Hybridization
• Mice
• Mutation (genetics)
• Nerve Tissue Proteins (genetics, metabolism)
• Oligonucleotides, Antisense (pharmacology)
• Peptide Fragments (genetics, metabolism)
• Trans-Activators (genetics)
• Transcription Factors (genetics, metabolism)
• Zebrafish (embryology, metabolism)