Abstract
Presentation Description :
Activating Transcription Factor 6 (ATF6) is a key regulator of endoplasmic reticulum homeostasis and cellular protein quality. Previously, we identified loss-of-function variants in patients that caused the heritable cone dysfunction disease achromatopsia. However, unlike other achromatopsia genes, ATF6 expression is not restricted to cones. Here, we report a sensorineural hearing defect found in some of our ATF6 variant patients. By contrast to the stationary cone dysfunction phenotype, hearing is initially normal but progressively worsens with age in ATF6 variant patients by audiogram testing. In ATF6-/- mice, hearing is also normal in 3-week old mice, but significant hearing loss at all frequencies is evident in 2-mo mice by audio brainstem recordings. Histologic evaluation of cochlea from ATF6 mutant mice reveals normal cochlear anatomy and no evidence of infection. Microscopic evaluation reveals loss of hair cells and pronounced disorganization of hair cell stereocilia in ATF6-/- mice. RNA-Seq reveals significant ER stress, ion channel dysregulation, and ER stress-induced cell death in hair cells of ATF6-/- mice. In sum, our findings identify a new phenotype - age-associated sensorineural hearing loss - arising from defects in the ATF6 proteostasis regulator. Our findings support that, in people, ATF6 disease variants, cause sensory loss syndrome arising from cone and hair cell dysfunction.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.