title: Achromatopsia mutations target sequential steps of ATF6 activation.
abstract: Achromatopsia is an autosomal recessive disorder characterized by cone photoreceptor dysfunction. We recently identified activating transcription factor 6 (ATF6) as a genetic cause of achromatopsia. ATF6 is a key regulator of the unfolded protein response. In response to endoplasmic reticulum (ER) stress, ATF6 migrates from the ER to Golgi to undergo regulated intramembrane proteolysis to release a cytosolic domain containing a basic leucine zipper (bZIP) transcriptional activator. The cleaved ATF6 fragment migrates to the nucleus to transcriptionally up-regulate protein-folding enzymes and chaperones. ATF6 mutations in patients with achromatopsia include missense, nonsense, splice site, and single-nucleotide deletion or duplication changes found across the entire gene. Here, we comprehensively tested the function of achromatopsia-associated ATF6 mutations and found that they group into three distinct molecular pathomechanisms: class 1 ATF6 mutants show impaired ER-to-Golgi trafficking and diminished regulated intramembrane proteolysis and transcriptional activity; class 2 ATF6 mutants bear the entire ATF6 cytosolic domain with fully intact transcriptional activity and constitutive induction of downstream target genes, even in the absence of ER stress; and class 3 ATF6 mutants have complete loss of transcriptional activity because of absent or defective bZIP domains. Primary fibroblasts from patients with class 1 or class 3 ATF6 mutations show increased cell death in response to ER stress. Our findings reveal that human ATF6 mutations interrupt distinct sequential steps of the ATF6 activation mechanism. We suggest that increased susceptibility to ER stress-induced damage during retinal development underlies the pathology of achromatopsia in patients with ATF6 mutations.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Chiang
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Chan
authors.affiliation: Institute for Ophthalmic Research, University of Tubingen, D-72076 Tubingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.affiliation: Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5T 3A9.
authors.forename: Ajoy
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, 60-806, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Skorczyk-Werner
authors.affiliation: Department of Medical Genetics, Poznan University of Medical Sciences, 60-806, Poznan, Poland.|Center for Medical Genetics GENESIS, 60-601, Poznan, Poland.
authors.forename: Maciej R
authors.initials: MR
authors.lastname: Krawczyński
authors.affiliation: Degenerative Diseases Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.|Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY 10032.|Departments of Ophthalmology, Pathology & Cell Biology, Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada M5T 3A9.
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
authors.affiliation: Institute for Ophthalmic Research, University of Tubingen, D-72076 Tubingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093; JLin@ucsd.edu.|VA San Diego Healthcare System, San Diego, CA 92161.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D003117:Color Vision Defects / Q000235:genetics* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D018832:Molecular Chaperones
keywords: ATF6; achromatopsia; cone photoreceptor; endoplasmic reticulum stress; unfolded protein response