Journal
NATURE GENETICS
Volume 47, Issue 7, Pages 757-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3319
Keywords
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Funding
- Bundesministerium fur Bildung und Forschung (BMBF) grant [01GM1108A]
- US National Institutes of Health [EY001919, EY020846, DK042394, DK088227, HL052173, 5P30EY019007]
- post-doctoral Foundation Fighting Blindness fellowship
- National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital, National Health Service (NHS) Foundation Trust
- University College London Institute of Ophthalmology, Fight For Sight, Moorfields Eye Hospital Special Trustees, Retinitis Pigmentosa Fighting Blindness
- Foundation Fighting Blindness (US)
- Wellcome Trust [099173/Z/12/Z]
- Foundation Fighting Blindness Career Development Award
- Mira Godard Research fund
- Cannon
- National Cancer Institute [5P30CA013696]
- Research to Prevent Blindness (RPB)
- Columbia University
- New York RPB Physician-Scientist Award
- Schneeweiss Stem Cell Fund, New York State [N09G-302, N13G-275]
- Gebroe Family Foundation [R01EY018213]
- Foundation Fighting Blindness (US) [BR-GE-0510-0489-RAD, C-GE-0811-0545-RAD01]
- Prof. Dr. H.J. Flieringa Foundation Stichting Wetenschappelijk Onderzoek het Oogziekenhuis (SWOO)
- Rotterdam Eye Hospital
- Center for Integrative Neuroscience-DFG Center of Excellence, University of Tubingen, Germany [EXC 307]
- Foundation Fighting Blindness (Canada)
- CIHR (Canadian Institutes for Health Research)
- Fight for Sight [1317/18, 24RP131] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10204] Funding Source: researchfish
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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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