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EW INTERNATIONAL 102 September 2015 by Matt Young and Gloria D. Gamat EyeWorld Contributing Writers Mutations in ATF6 gene open future treatment pathway for achromatopsia G erman researchers, in col- laboration with American, Italian, Dutch, British, and Canadian scientists, have recently discovered genetic mutations that elucidate the mechanism of achromatopsia, a rare genetic disorder characterized by a lack of cone photoreceptor function (hence, the absence of or severely reduced color and daytime vision). Using gene sequencing in pa- tients, the research team found that mutations in the ATF6 gene (activat- ing transcription factor 6A) can lead to disease development. The ATF6 gene is the 6th gene found to be related to achroma- topsia, adding to the 5 previously identified genes (CNGA3, CNGB3, PDE6C, PDE6H, and GNAT2), which accounted for roughly 75% of all cases. The new findings, reported in the June 2015 issue of Nature Genetics, can potentially bring about specialized treatments for this rare type of color blindness. "All genes known to be associat- ed with achromatopsia are com- ponents of the phototransduction cascade in the cone photoreceptor," said Susanne Kohl, PhD, group leader, lecturer, and associated head, Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Germany. The current treatment for all forms, including ATF6-achromatop- sia, Dr. Kohl noted, is only symp- tomatic assistance: "dark or special filter glasses or red-tinted contact lenses to reduce photophobia and potentially improve visual acuity, low vision aids, and occupational aids." Unlike typical color blindness that cannot distinguish between red and green, patients suffering from achromatopsia see the world in black, white, and shades of grey, with severely reduced visual acuity, nystagmus (uncontrolled eye move- ment), and marked photophobia (sensitivity to light). Achromatopsia affects 1 person out of every 30,000 people globally. However, Dr. Kohl emphasized that this incidence rate is related to Cau- casian patients (patients of Northern European descent). "There is a small Micronesian island called Pingelap on which achromatopsia is much more frequent [about 10% of the popu- lation], due to a founder mutation in the CNGB3 gene," she said. The story is long-known and described in a book by Oliver Sacks, The Island of the Colorblind. Usually presenting from birth or early infancy, the achromatop- sia diagnosis can be tricky for any clinician. "The patients will present with nystagmus and/or photophobia within a few weeks or months after birth—these are typically the very first symptoms," Dr. Kohl said. While an experienced ophthal- mologist that is aware of this disor- der might then propose achroma- topsia as a diagnosis, at that young age of the patient, according to Dr. Kohl, other clinical diagnoses have to be considered as well (i.e., con- genital nystagmus, Leber congenital amaurosis). "Clinically, the diagnosis can only be confirmed later in life by a color vision test, visual acuity test and electroretinography," Dr. Kohl said. "Genetically, the diagnosis can be confirmed right after the first symptoms have been observed and a tentative diagnosis has been proposed." The role of the ATF6 gene For a rare condition with currently no effective treatment, the discovery of a directly linked genetic mutation could help identify potential thera- peutic agents in the future. ATF6 is a key regulator of the unfolded protein response (UPR) pathway, a critical mechanism that cells use to subvert buildup of unfolded or misfolded proteins. An ATF6 gene mutation disrupts the UPR process and causes the produc- tion of bad proteins, which leads to the malfunction of cone photore- ceptors. In the Nature Genetics paper, the researchers reported: "This new achromatopsia-related gene suggests a crucial and unexpected role for ATF6A in human foveal develop- ment and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype." Based on animal research, the group suggested that the cone cells of people with achromatopsia are not injured forever. They may be renewed by optimizing the pathway that regulates the UPR. "The impact of the discov- ery of this gene [ATF6] is that it would never have been considered a candidate gene for this disorder from its known biological func- tion as a key regulator in the UPR pathway [which also has an import- ant function in the retina and the photoreceptors], but why a defect in this protein results in a pure cone photoreceptor disorder remains to be elucidated," Dr. Kohl said. Discovery of new gene mutation sheds light on rare color blindness G enetic research continues to open new possibilities for the treatment of ocular disease. In this article we describe how a dedicated team of research- ers has discovered the genetic basis of a rare form of color blindness. Understanding a disease process is a prerequisite step to developing a cure. There is reason to hope that this discovery may someday help improve the quality of life of those who are affected. While achromatopsia is a rare condition, the benefit of understanding the genetics of cone photoreceptors adds another piece to our understanding of the visual system. John A. Vukich, MD, international editor International outlook

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