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

Nature Genetics volume 47, pages 757–765 (2015)Cite this article

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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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Figure 1: Families, ATF6 genotypes and cDNA analysis.
Figure 2: Functional and morphological presentation of patients carrying mutations in ATF6.
Figure 3: Montages of AOSLO imaging of individual cones from the right eye of patient CHRO628-II:2.
Figure 4: Functional analysis in human fibroblasts and HEK293 cells shows defective transcriptional activity for the Arg324Cys ATF6A mutant.
Figure 5: Functional and morphological presentation of Atf6−/− and Atf6+/+ mice.
Figure 6: Topography of ATF6A and the location of the disease-causing variants identified in patients with ACHM.

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Change history

  • 15 June 2015

    In the version of this article initially published online, the ATF6 protein alteration corresponding to the smaller aberrantly spliced band resulting from the variant c.1533+1G>C was incorrectly reported as p.Gly512Valfs*11 on page 3 of the PDF and in the legend for Figure 6. The correct protein alteration is p.Leu479Valfs*11. The same error occurred in Table 1 for the following five patients: CHRO593-IV:1, CHRO593-II:3, MOGL411-MOGL467-III:4, MOGL411-MOGL467-IV:1 and MOGL5414-II:1. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We want to thank C.W. Seok for data analysis. These studies were supported by various grants to the different authors and institutions: Bundesministerium für Bildung und Forschung (BMBF) grant 01GM1108A to B.W. and S.K.; US National Institutes of Health grants EY001919 and EY020846 to J.H.L. and DK042394, DK088227 and HL052173 to R.J.K. and a post-doctoral Foundation Fighting Blindness fellowship to W.-C.C.; National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital, National Health Service (NHS) Foundation Trust and University College London Institute of Ophthalmology, Fight For Sight, Moorfields Eye Hospital Special Trustees, Retinitis Pigmentosa Fighting Blindness and the Foundation Fighting Blindness (US) all to A.T.M., M.M. and A.R.W.; and the Wellcome Trust (099173/Z/12/Z) to M.M. and A.R.W. M.M. is supported by a Foundation Fighting Blindness Career Development Award; Mira Godard Research fund to E.H.; the imaging facilities at the Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and the Bernard and Shirlee Brown Glaucoma Laboratory are supported by Cannon, US National Institutes of Health Core grant 5P30EY019007, National Cancer Institute Core grant 5P30CA013696 and unrestricted funds from Research to Prevent Blindness (RPB), a Columbia University, New York RPB Physician-Scientist Award, the Schneeweiss Stem Cell Fund, New York State (N09G-302 and N13G-275) and the Gebroe Family Foundation, grant R01EY018213 to S.H.T.; Foundation Fighting Blindness (US) grants BR-GE-0510-0489-RAD to A.I.d.H. and C-GE-0811-0545-RAD01 to F.P.M.C., the Prof. Dr. H.J. Flieringa Foundation Stichting Wetenschappelijk Onderzoek het Oogziekenhuis (SWOO) and the Rotterdam Eye Hospital to F.P.M.C. and A.I.d.H. E.Z. is supported by Center for Integrative Neuroscience–DFG Center of Excellence EXC 307, University of Tübingen, Germany. R.K.K. is supported by the Foundation Fighting Blindness (Canada) and the CIHR (Canadian Institutes for Health Research).

Author information

Authors and Affiliations

  1. Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany

    Susanne Kohl, Ditta Zobor, Nicole Weisschuh, Jennifer Staller, Irene Gonzalez Menendez, Susanne C Beck, Marina Garcia Garrido, Vithiyanjali Sothilingam, Mathias W Seeliger, Eberhart Zrenner & Bernd Wissinger

  2. Department of Pathology, University of California, San Diego, La Jolla, California, USA.,

    Wei-Chieh Chiang & Jonathan H Lin

  3. Department of Ophthalmology, Columbia University, New York, New York, USA

    Stanley Chang & Stephen H Tsang

  4. Edward Harkness Eye Institute, New York Presbyterian Hospital, New York, New York, USA

    Stanley Chang

  5. Clinical Genetics Service, Regional Hospital Bozen, Bozen, Italy

    Franco Stanzial, Francesco Benedicenti & Francesca Inzana

  6. Department of Ophthalmology and Vision Sciences, Programme of Genetics and Genomic Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Elise Héon & Ajoy Vincent

  7. Medical Genetics, IWK Health Centre, Halifax, Nova Scotia, Canada

    Jill Beis

  8. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    Tim M Strom

  9. Institute of Human Genetics, Technische Universität München, Munich, Germany

    Tim M Strom

  10. University Eye Hospital, Ludwig Maximilians University, Munich, Germany

    Günther Rudolph

  11. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands

    Susanne Roosing, Anneke I den Hollander & Frans P M Cremers

  12. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands

    Anneke I den Hollander

  13. McGill Ocular Genetics Centre, McGill University Health Centre, Montreal, Quebec, Canada

    Irma Lopez, Huanan Ren & Robert K Koenekoop

  14. University College London Institute of Ophthalmology, University College London, London, UK

    Anthony T Moore, Andrew R Webster & Michel Michaelides

  15. Moorfields Eye Hospital, London, UK

    Anthony T Moore, Andrew R Webster & Michel Michaelides

  16. Ophthalmology Department, University of California San Francisco Medical School, San Francisco, California, USA

    Anthony T Moore

  17. Werner Reichardt Center for Integrative Neuroscience, University of Tübingen, Tübingen, Germany

    Eberhart Zrenner

  18. Degenerative Diseases Program, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

    Randal J Kaufman

  19. Jonas Laboratory of Stem Cell and Regenerative Medicine, Columbia University, New York, New York, USA

    Stephen H Tsang

  20. Brown Glaucoma Laboratory, Columbia University, New York, New York, USA

    Stephen H Tsang

  21. Institute of Human Nutrition, Columbia University, New York, New York, USA

    Stephen H Tsang

  22. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA

    Stephen H Tsang

  23. Department of Ophthalmology, University of California, San Diego, La Jolla, California, USA

    Jonathan H Lin

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Contributions

S.K., B.W., J.H.L. and R.J.K. conceived and designed the project and analyzed and interpreted data. D.Z., F.S., F.B., F.I., E.H., A.V., J.B., G.R., A.T.M., A.W., M.M., R.K.K., E.Z. and S.H.T. provided clinical data collection and interpretation. N.W., J.S., W.-C.C., S.R., A.I.d.H., F.P.M.C., I.L. and H.R. designed and performed experiments and analyzed and interpreted data. Specifically, N.W. performed cDNA analysis and haplotyping. J.S. performed all candidate gene sequencing. I.G.M. performed mouse retinal histology. T.M.S. was responsible for exome sequencing. S.C. and S.H.T. provided the AOSLO data. S.C.B., M.G.G., V.S. and M.W.S. provided the in vivo morphological and functional analyses of the mouse model, data generation and analysis, and writing of the manuscript. S.K., J.H.L. and D.Z. drafted the manuscript. M.M., R.K.K., E.H., A.V., A.T.M., A.W., M.M. and R.K.K. critically revised the manuscript for intellectual content. All authors discussed the results and commented on the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Susanne Kohl or Jonathan H Lin.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Electropherograms of all identified mutations in ATF6.

Mutant sequence (top) compared to wild-type sequence (bottom). Nucleotide and protein sequence (one-letter code) are presented beneath the electropherogram. Exonic sequence is given in uppercase letters, and intronic sequence is given in lowercase letters. Arrows indicate the mutation.

Supplementary Figure 2 Comparative sequence analysis showing conservation of ATF6A at the protein level.

Comparative sequence analysis showing conservation of ATF6A at the protein level according to HomoloGene. In addition, alignment with human ATF6B is shown on the last line for comparison. Top, protein alignment for the p.Arg324Cys missense mutation. Bottom, protein alignment for the p.Tyr567Asn mutation.

Supplementary Figure 3 Atf6−/− mouse whole-mount and biochemistry data.

(a) Whole-mount retina preparations from 1-year-old Atf6+/– and Atf6−/− mice were stained with FITC-PNA (left immunofluorescent images), and the numbers of FITC-PNA–positive cone cells were quantified with Keyence BZ image analysis software for eight different eyes. Scale bar, 500 µm. (b–d) Whole retinas were collected and lysed from 90-d-old wild-type, Atf6+/– and Atf6−/− mice (n = 4 per genotype). (b) Cone-specific proteins (M opsin, S opsin and glycogen phosphorylase), (c) rod-specific proteins (rhodopsin and Gαt1 / rod transducin) and (d) ER stress-induced proteins (PDI, calreticulin and BiP (Grp78)) were detected by immunoblotting. HSP90 served as a protein loading control. WT, wild type; FITC, fluorescein isothiocyanate; PNA, peanut agglutinine.

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Kohl, S., Zobor, D., Chiang, WC. et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet 47, 757–765 (2015). https://doi.org/10.1038/ng.3319

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