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

Nat Genet. 2015 Jul;47(7):757-65. doi: 10.1038/ng.3319.

Susanne Kohl ¹, Ditta Zobor ¹, Wei-Chieh Chiang ², Nicole Weisschuh ¹, Jennifer Staller ¹, Irene Gonzalez Menendez ¹, Stanley Chang ³, Susanne C Beck ¹, Marina Garcia Garrido ¹, Vithiyanjali Sothilingam ¹, Mathias W Seeliger ¹, Franco Stanzial ⁴, Francesco Benedicenti ⁴, Francesca Inzana ⁴, Elise Héon ⁵, Ajoy Vincent ⁵, Jill Beis ⁶, Tim M Strom ⁷, Günther Rudolph ⁸, Susanne Roosing ⁹, Anneke I den Hollander ¹⁰, Frans P M Cremers ⁹, Irma Lopez ¹¹, Huanan Ren ¹¹, Anthony T Moore ¹², Andrew R Webster ¹³, Michel Michaelides ¹³, Robert K Koenekoop ¹¹, Eberhart Zrenner ¹⁴, Randal J Kaufman ¹⁵, Stephen H Tsang ¹⁶, Bernd Wissinger ¹, Jonathan H Lin ¹⁷

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.

PMID: 26029869 DOI: 10.1038/ng.3319

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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