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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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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

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Susanne Kohl or Jonathan H Lin.

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https://doi.org/10.1038/ng.3319

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