Schönberger Jost, Wang Libin, Shin Jordan T, Kim Sang Do, 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
Harvard Medical School, Department of Genetics, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Nat Genet. 2005 Apr;37(4):418-22. doi: 10.1038/ng1527. Epub 2005 Feb 27.
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.
我们鉴定出一种人类突变，该突变会导致扩张型心肌病和心力衰竭，且之前伴有感音神经性听力损失（SNHL）。与先前描述的导致扩张型心肌病的影响结构蛋白的突变不同，此突变缺失了人类转录共激活因子基因EYA4的4846 bp。为阐明eya4在心脏功能中的作用，我们研究了注射反义吗啉代寡核苷酸的斑马鱼胚胎。eya4转录本水平降低产生了心力衰竭的形态学和血流动力学特征。为确定为何先前描述的突变EYA4等位基因会导致无心脏病的SNHL，我们检测了突变Eya4肽的生化相互作用。与SNHL相关的Eya4肽，而非与扩张型心肌病和SNHL相关的缩短的193个氨基酸的肽，与野生型Eya4结合并与Six蛋白相关。这些数据确定了Eya4 - Six介导的转录调控在正常心脏功能中未被认识到的关键作用。
