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      Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.

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          Abstract

          Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.

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          Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1.

          Keisuke Yamamoto, Takashi Sato, Toshie Matsui … (2007)
          Metazoans express three unfolded protein response transducers (IRE1, PERK, and ATF6) ubiquitously to cope with endoplasmic reticulum (ER) stress. ATF6 is an ER membrane-bound transcription factor activated by ER stress-induced proteolysis and has been duplicated in mammals. Here, we generated ATF6alpha- and ATF6beta-knockout mice, which developed normally, and then found that their double knockout caused embryonic lethality. Analysis of mouse embryonic fibroblasts (MEFs) deficient in ATF6alpha or ATF6beta revealed that ATF6alpha is solely responsible for transcriptional induction of ER chaperones and that ATF6alpha heterodimerizes with XBP1 for the induction of ER-associated degradation components. ATF6alpha(-/-) MEFs are sensitive to ER stress. Unaltered responses observed in ATF6beta(-/-) MEFs indicate that ATF6beta is not a negative regulator of ATF6alpha. These results demonstrate that ATF6alpha functions as a critical regulator of ER quality control proteins in mammalian cells, in marked contrast to worm and fly cells in which IRE1 is responsible.
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            The impact of the unfolded protein response on human disease

            Shiyu Wang, Randal Kaufman (2012)
            A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.
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              ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress.

              Jun Wu, D. Rutkowski, Meghan Dubois … (2007)
              In vertebrates, three proteins--PERK, IRE1alpha, and ATF6alpha--sense protein-misfolding stress in the ER and initiate ER-to-nucleus signaling cascades to improve cellular function. The mechanism by which this unfolded protein response (UPR) protects ER function during stress is not clear. To address this issue, we have deleted Atf6alpha in the mouse. ATF6alpha is neither essential for basal expression of ER protein chaperones nor for embryonic or postnatal development. However, ATF6alpha is required in both cells and tissues to optimize protein folding, secretion, and degradation during ER stress and thus to facilitate recovery from acute stress and tolerance to chronic stress. Challenge of Atf6alpha null animals in vivo compromises organ function and survival despite functional overlap between UPR sensors. These results suggest that the vertebrate ATF6alpha pathway evolved to maintain ER function when cells are challenged with chronic stress and provide a rationale for the overlap among the three UPR pathways.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat. Genet.
                Title: Nature genetics
                ISSN (Electronic): 1546-1718
                ISSN (Print): 1061-4036
                Publication date (Electronic): Jul 2015
                Volume: 47
                Issue: 7
                Affiliations
                [1 ] Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
                [2 ] Department of Pathology, University of California, San Diego, La Jolla, California, USA.
                [3 ] 1] Department of Ophthalmology, Columbia University, New York, New York, USA. [2] Edward Harkness Eye Institute, New York Presbyterian Hospital, New York, New York, USA.
                [4 ] Clinical Genetics Service, Regional Hospital Bozen, Bozen, Italy.
                [5 ] Department of Ophthalmology and Vision Sciences, Programme of Genetics and Genomic Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
                [6 ] Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada.
                [7 ] 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
                [8 ] University Eye Hospital, Ludwig Maximilians University, Munich, Germany.
                [9 ] Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
                [10 ] 1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. [2] Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
                [11 ] McGill Ocular Genetics Centre, McGill University Health Centre, Montreal, Quebec, Canada.
                [12 ] 1] University College London Institute of Ophthalmology, University College London, London, UK. [2] Moorfields Eye Hospital, London, UK. [3] Ophthalmology Department, University of California San Francisco Medical School, San Francisco, California, USA.
                [13 ] 1] University College London Institute of Ophthalmology, University College London, London, UK. [2] Moorfields Eye Hospital, London, UK.
                [14 ] 1] Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany. [2] Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
                [15 ] Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
                [16 ] 1] Department of Ophthalmology, Columbia University, New York, New York, USA. [2] Jonas Laboratory of Stem Cell and Regenerative Medicine, Columbia University, New York, New York, USA. [3] Brown Glaucoma Laboratory, Columbia University, New York, New York, USA. [4] Institute of Human Nutrition, Columbia University, New York, New York, USA. [5] Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
                [17 ] 1] Department of Pathology, University of California, San Diego, La Jolla, California, USA. [2] Department of Ophthalmology, University of California, San Diego, La Jolla, California, USA.
                Article
                Publisher Item ID: ng.3319 Mid ID: NIHMS728805
                DOI: 10.1038/ng.3319
                PubMed ID: 26029869
                SO-VID: e1f313e3-fa5b-4381-84a3-5c1c863893ff
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