New color blindness cause identified: Finding suggests potential therapeutic targets

The researchers found that mutations to a gene called ATF6, a key regulator of the unfolded protein response, can lead to achromatopsia, a hereditary visual disorder characterized by color blindness, decreased vision, light sensitivity, and uncontrolled eye movement in children.

The unfolded protein response is a mechanism cells use to prevent the dangerous accumulation of unfolded or mis-folded proteins.

Based on mouse studies, the researchers suspect that the cone cells of people with achromatopsia are not permanently damaged and could be revived by enhancing the pathway that regulates the unfolded protein response. "Several drugs that activate this pathway have already been approved by the FDA for other conditions and could potentially benefit patients with achromatopsia," said one of the study leaders, Stephen Tsang, MD, PhD, who is the Laszlo Z. Bito Associate Professor of Ophthalmology, and is affiliated with the Institute of Human Nutrition, at CUMC.

"Dr. Tsang's innovative research continues to unfold the genetic basis for a variety of ocular diseases. This finding is an example of the finest clinically based science that will ultimately allow us to overcome preventable vision loss," said George A. Cioffi, MD, Edward S. Harness Chairman and Ophthalmologist-in-Chief at NewYork-Presbyterian Hospital/Columbia University Medical Center.

"Five genes had previously been linked to achromatopsia; however, they accounted for only about half of all cases," said Dr. Tsang. "Using next-generation gene sequencing on a small group of patients, we found that mutations in a sixth gene -- ATF6 -- can independently lead to the disease."

Dr. Tsang is also associate professor of pathology and cell biology at CUMC and an attending physician at NewYork-Presbyterian Hospital.

Mutations in ATF6 (activating transcription factor 6A) have been implicated in other conditions, including diabetes and Alzheimer disease models, but this is the first time that they have been directly linked to human disease.

Achromatopsia, famously described by Oliver Sacks in his book Island of the Colorblind, affects an estimated one in 30,000 people worldwide. It is a disorder of the retina's cone cells, which provide vision in daylight, including color vision. Rod cells, which provide vision in dim light, are unaffected. There is currently no effective treatment for the disease, which appears in infancy and typically does not progress. Ophthalmologists prescribe specially-filtered dark glasses or red-tinted contact lenses to reduce light sensitivity and with the intention of improving visual acuity.

The new mutations were initially identified by sequencing the exomes (protein-coding portions of the genome) of three children with achromatopsia who receive their care at NYPH. None of the children had mutations in the five known achromatopsia genes. ATF6 mutations were subsequently observed in 15 achromatopsia patients from nine other families in the study. All of the patients were found to have significant fovea hypoplasia (an underdevelopment of the macula, the center of the retina), a characteristic not commonly seen in other achromatopsia patients.

By analyzing skin cells from achromatopsia patients and their unaffected family members, the researchers confirmed that the ATF6 mutations were interfering with the signaling pathway that regulates the unfolded protein response. Surprisingly, the patients had no other ATF6-related abnormalities. "ATF6 is found in every cell of the body, but for some reason only the cone cells were affected," said Dr. Tsang.

The researchers estimate that ATF6 mutations account for only about one percent of cases of the disease. "As we sequence more and more achromatopsia patients, we're likely to identify other genes," said Dr. Tsang. "I think the important lesson of this study is that it demonstrates how advanced technologies are bringing precision medicine to the field of ophthalmology. Certain diseases may look the same based on the clinical diagnosis, but we're finding that each patient is a little bit different and may benefit from a personalized approach to treatment."

The paper is titled, "Mutations in the Unfolded Protein Response Regulator, ATF6, Cause the cone Cone dysfunction Dysfunction Syndrome Achromatopsia." The other contributors are: Susanne Kohl (University of Tuebingen, Tuebingen, Germany), Ditta Zobor (University of Tuebingen), Wei-Chieh Chiang (University of California San Diego, La Jolla, CA), Nicole Weisschuh (University of Tuebingen), Jennifer Staller (University of Tuebingen), Irene Gonzalez Menendez (University of Tuebingen), Stanley Chang (CUMC), Susanne C. Beck (University of Tuebingen), Marina Garcia Garrido (University of Tuebingen), Vithiyanjali Sothilingam (University of Tuebingen), Mathias W. Seeliger (University of Tuebingen), Franco Stanzial (Regional Hospital Bozen, Italy), Francesco Benedicenti (Regional Hospital Bozen), Francesca Inzana (Regional Hospital Bozen), Elise Héon (University of Toronto, Toronto, ON, Canada), Ajoy Vincent (University of Toronto), Jill Beis (IWK Health Centre, Halifax, Canada), Tim M. Strom (Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany, and Institute of Human Genetics, Technische Universität München, Munich, Germany), Günther Rudolph (University Eye Hospital, Munich, Germany), Susanne Roosing (Radboud University Medical Center), Anneke I. den Hollander (Radboud University Medical Center), Frans P.M. Cremers (Radboud University Medical Center), Irma Lopez (McGill University Health Centre, Montreal, Canada), Huanan Ren (McGill University Health Centre), Anthony T. Moore (University College London, London, UK; Moorfields Eye Hospital, London, UK; and UCSF Medical School, San Francisco, CA), Andrew Webster (University College London and Moorfields Eye Hospital), Michel Michaelides (University College London and Moorfields Eye Hospital), Robert K. Koenekoop (McGill University Health Centre), Eberhart Zrenner (University of Tuebingen), Randal J. Kaufman (Sanford Burnham Medical Research Institute, La Jolla, CA), Bernd Wissinger (University of Tuebingen), and Jonathan H. Lin (University of California San Diego).

The study was funded by grants from Federal Ministry of Education and Research, Germany; National Institutes of Health (EY018213, EY001919, EY020846, DK042394, DK088227, and HL052173); Foundation Fighting Blindness; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital; NHS Foundation Trust; UCL Institute of Ophthalmology; Fight For Sight; Moorfields Eye Hospital Special Trustees; and Barbara & Donald Jonas Laboratory of Stem Cells and Regenerative Medicine, Bernard & Shirlee Brown Glaucoma Laboratory, the Joan and Michael Schneeweiss Stem Cell Fund and Research to Prevent Blindness.

The authors declare no financial or other conflicts of interest.