title: Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.
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.
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Ditta
authors.initials: D
authors.lastname: Zobor
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Chiang
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Weisschuh
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Staller
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Gonzalez Menendez
authors.affiliation: 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.
authors.forename: Stanley
authors.initials: S
authors.lastname: Chang
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.affiliation: Clinical Genetics Service, Regional Hospital Bozen, Bozen, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Stanzial
authors.affiliation: Clinical Genetics Service, Regional Hospital Bozen, Bozen, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedicenti
authors.affiliation: Clinical Genetics Service, Regional Hospital Bozen, Bozen, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Inzana
authors.affiliation: Department of Ophthalmology and Vision Sciences, Programme of Genetics and Genomic Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Héon
authors.affiliation: Department of Ophthalmology and Vision Sciences, Programme of Genetics and Genomic Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ajoy
authors.identifier: 0000000164463846
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: Jill
authors.initials: J
authors.lastname: Beis
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: University Eye Hospital, Ludwig Maximilians University, Munich, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Rudolph
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.affiliation: 1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. [2] Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke I den
authors.initials: AI
authors.lastname: Hollander
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: McGill Ocular Genetics Centre, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.affiliation: McGill Ocular Genetics Centre, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.affiliation: 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.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: 1] University College London Institute of Ophthalmology, University College London, London, UK. [2] Moorfields Eye Hospital, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: 1] University College London Institute of Ophthalmology, University College London, London, UK. [2] Moorfields Eye Hospital, London, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: McGill Ocular Genetics Centre, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: 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.
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.affiliation: Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: 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.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.affiliation: 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.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D003117:Color Vision Defects / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D014158:Transcription, Genetic; D056811:Unfolded Protein Response; D055815:Young Adult
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6