Achromatopsia is a heritable, blinding disease characterized by cone photoreceptor dysfunction and retinal degeneration. Using next-generation sequencing, we discovered novel mutations in the ATF6 gene in patients with achromatopsia. ATF6 is an important regulator of the Unfolded Protein Response, an intracellular molecular mechanism that protects cells from protein misfolding and endoplasmic reticulum stress. The function of ATF6 in photoreceptors and the mechanism by which human ATF6 mutations cause cone dysfunction, photoreceptor cell death, and achromatopsia are unknown. The objective of this proposal is to determine how ATF6 regulates photoreceptor cell survival, and why mutations in ATF6 cause retinal degeneration in patients. To understand the role of ATF6 stress in retinal degeneration, we will: 1. Determine the role of ATF6 in human retinal development, 2. Determine the mechanism of retinal degeneration in Atf6-/- mice. 3. Identify the biochemical mechanism for the pathogenicity of human ATF6 mutations. ATF6 is a novel gene required for healthy retinal function in people. Our research is expected to elucidate the function of ATF6 in photoreceptors under normal and diseased conditions. Our studies will have a positive impact by revealing why ATF6 mutations cause vision loss and identify new environmental and pharmacologic strategies to prevent retinal degeneration in affected individuals.
ATF6 is a novel gene that causes the cone photoreceptor disease, achromatopsia, when mutated in patients. This project investigates the function of ATF6 in the retina and how human ATF6 mutations lead to vision loss.
|Kroeger, Heike; Grimsey, Neil; Paxman, Ryan et al. (2018) The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Sci Signal 11:|