EYA4突变致DFNA10型遗传性耳聋的研究进展

Advances in Research on DFNA10 Hereditary Hearing Loss Caused by EYA4 Mutations

EYA4(Eye absent 4)(OMIM:603550)基因是Eya家族蛋白中的一员,编码转录激活因子相关蛋白,在胚胎发育过程中对组织特异性分化具有重要调控作用。EYA4蛋白含有高度保守的eyaHR和非保守的eyaVR两个功能域,eyaHR参与SIX/DACH蛋白之间的相互作用;eyaVR参与转录激活及机体固有免疫功能。EYA4致病突变会导致DFNA10型遗传性耳聋,临床表现为双侧对称的、迟发性、进展性感音神经性听力损失,发病初期常累及中频听力,呈谷型或平坦型听力曲线。目前已在世界范围内报道与DFNA10型耳聋相关EYA4的18种致病突变,多数突变引起EYA4翻译提前终止形成截短蛋白,单倍体剂量不足导致的失能效应是EYA4致聋的原因,EYA4的下调会引起内耳细胞的Na+/K+-ATP酶功能异常进而导致听觉障碍。构建合适的动物模型、鉴定更多的致病突变位点及深入的功能实验有助于进一步探索EYA4精确的致聋机制。

EYA4(Eye absent 4)is a member of the vertebrate Eya gene family of transcriptional activators and plays an important role in regulating tissue specific differentiation during embryonic development.The EYA4 protein contains a highly conserved domain(eyaHR)and a variable domain(eyaVR).The eyaHR is involved in binding the SIX/DACH proteins and the eyaVR is responsible for transcriptional activation and innate immune.EYA4 pathogenic mutation can result in DFNA10 hereditary deafness,which is characterized by bilateral symmetric,postlingual-onset and progressive hearing loss and initially involves mid-frequency hearing,presenting a valley or flat audiogram curve.There have been 18 types of mutations reported worldwide so far,most of which causing premature termination of EYA4 protein synthesis to generate truncated proteins.The loss of function due to EYA4 haplo insufficiency may account for the DFNA10 hearing loss,which may disturb normal function of Na^+/K^+-ATP enzymes in inner ear cells.The precise mechanism of hearing loss caused by EYA4 is not yet clear,which will require appropriate animal models,identification of additional pathogenic mutation sites and in depth functional studies.