Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome

Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear. In light of the broad range of organs impacted by a loss of ATF6 in experimental animal models, we investigated whether patients lacking functional ATF6 had additional diseases or phenotypes beyond the previously reported vision loss. We also characterized the cellular and molecular defects in the ear that underlie the hearing loss in the Atf6-/- mice.激活转录因子6（Activating transcription factor 6，Atf6）是未折叠蛋白反应（unfolded protein response，UPR）的关键调控因子，对多细胞动物细胞的内质网（endoplasmic reticulum，ER）功能与蛋白质稳态至关重要。携带功能丧失型ATF6疾病等位基因的患者会罹患视锥细胞功能障碍性疾病——全色盲（achromatopsia）。目前，ATF6功能丧失对人体其他细胞类型、器官及疾病的影响仍不明确。本研究发现，部分携带ATF6疾病等位基因的患者存在显著的进行性感音神经性听力损失；同时，Atf6基因敲除（Atf6-/-）小鼠也表现出累及两性的进行性听觉功能缺陷。在存在听觉缺陷的小鼠中，我们观察到毛细胞的静纤毛排列紊乱，且外毛细胞出现局灶性丢失。对Atf6-/-小鼠耳蜗的转录组分析显示，UPR通路被显著激活，尤其是通过PERK通路分支。上述研究结果确认ATF6是维持耳蜗健康与功能的关键调控因子。此外，本研究证实，人体内ATF6失活会导致进行性感音神经性听力损失，这是一种以毛细胞与视锥感光细胞为靶标的盲-聋遗传综合征的临床表现之一。最后，我们的遗传学研究结果表明，内质网应激是耳蜗损伤与听力损失的重要致病机制，这为临床通过调整患者生活方式、减少耳部暴露于环境/生理源性内质网应激的机会提供了理论依据。鉴于实验动物模型中ATF6功能丧失会广泛影响多个器官，我们进一步探究了功能性ATF6缺失的患者是否存在此前已报道的视力丧失之外的其他疾病或表型，并对Atf6-/-小鼠听力损失背后的耳部细胞与分子缺陷进行了系统表征。