Scientists find gene mutation linked to exfoliation syndrome, most common cause of glaucoma
- Date:
- May 4, 2021
- Source:
- Agency for Science, Technology and Research (A*STAR), Singapore
- Summary:
- A team of researchers have identified a genetic mutation associated with exfoliation syndrome, characterized by abnormal protein material accumulating in the front of the eye. It is the most common cause of glaucoma, and a major cause of irreversible blindness. The findings could lead to further research on the causes of the systemic disorder and potential cures.
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A team of researchers from the Agency for Science, Technology and Research's (A*STAR) Genome Institute of Singapore (GIS) and Bioprocessing Technology Institute (BTI), as well as Singapore Eye Research Institute (SERI), have identified a genetic mutation (functionally defective CYP39A1 gene) associated with exfoliation syndrome, the most common cause of glaucoma. The findings could pave the way for future research on the cause of exfoliation syndrome and potential cures. Their research was published in Journal of the American Medical Association (JAMA) on 24 February 2021.
Exfoliation syndrome is a systemic disorder characterised by abnormal protein material that progressively accumulates in the front of the eye. This disorder is the most common cause of glaucoma, and a major cause of irreversible blindness.
In this study, the scientists sequenced all protein encoding genes of more than 20,000 participants from 14 countries across Asia, Europe, and Africa, including more than 1,200 Singaporeans. They observed that people with exfoliation syndrome are twice as likely to carry damaging mutations in the gene encoding for the CYP39A1 protein, an enzyme which plays an important role in the processing of cholesterol. Further extended analyses suggest that defective CYP39A1 function is strongly associated with increased risk of exfoliation syndrome.
Although exfoliation syndrome is the most common cause of glaucoma, its origin is shrouded in mystery because it is not known where the abnormal protein deposits (exfoliative material) originate, and how the disease comes about. Answers to these questions could provide approaches to design and develop an effective treatment. The current findings point to the important role of cholesterol processing in the exfoliation syndrome disease process. As cholesterol is found abundantly in all cells, disruption to how cholesterol is processed due to defective CYP39A1 activity could adversely impact their normal functions. In particular, this study discovered that epithelial cells in the front of the eye responsible for filtering the blood supply to produce the clear fluid known as aqueous humour that bathes and nourishes other cells in the eye, were most affected by the CYP39A1 gene mutation. Disruption to the gene function can compromise the filtering function of epithelial cells and lead to leakage of exfoliative material from the blood into the eye.
Prof Patrick Tan, Executive Director of GIS, said, "This is a ground-breaking study that could facilitate future research efforts aimed at restoring defective CYP39A1 function and inhibiting the formation of exfoliation material in the eye as treatments for exfoliation syndrome and glaucoma."
Prof Aung Tin, Director of SERI and Deputy Medical Director of SNEC, said, "This is a major eye disease, affecting over 70 million people worldwide, which causes a lot of visual morbidity and blindness, not only from glaucoma but also due to complications related to cataract surgery. This study was notable for involving many centres from many different countries around the world, but led from Singapore. The study findings are very exciting as we found a new pathway for the disease which opens up possibilities for new treatments."
Prof David Friedman, the Albert and Diane Kaneb Chair in Ophthalmology at Harvard University and Director of the Glaucoma Service at the Massachusetts Eye and Ear Infirmary, Boston, commented, "Very exciting work. The researchers have identified rare gene variants that results in disrupted cholesterol homeostasis and transport that will open the door to novel therapeutics. Having studied over 20,000 individuals, the study demonstrates the power of studying rare variants to detect disease-causing genes in complex conditions." Prof Friedman was not involved in the study.
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Materials provided by Agency for Science, Technology and Research (A*STAR), Singapore. Note: Content may be edited for style and length.
Journal Reference:
- Zheng Li, Zhenxun Wang, Mei Chin Lee, Matthias Zenkel, Esther Peh, Mineo Ozaki, Fotis Topouzis, Satoko Nakano, Anita Chan, Shuwen Chen, Susan E. I. Williams, Andrew Orr, Masakazu Nakano, Nino Kobakhidze, Tomasz Zarnowski, Alina Popa-Cherecheanu, Takanori Mizoguchi, Shin-ichi Manabe, Ken Hayashi, Shigeyasu Kazama, Kenji Inoue, Yosai Mori, Kazunori Miyata, Kazuhisa Sugiyama, Tomomi Higashide, Etsuo Chihara, Ryuichi Ideta, Satoshi Ishiko, Akitoshi Yoshida, Kana Tokumo, Yoshiaki Kiuchi, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Makoto Aihara, Masaru Inatani, Kazuhiko Mori, Yoko Ikeda, Morio Ueno, Daniel Gaston, Paul Rafuse, Lesya Shuba, Joseph Saunders, Marcelo Nicolela, George Chichua, Sergo Tabagari, Panayiota Founti, Kar Seng Sim, Wee Yang Meah, Hui Meng Soo, Xiao Yin Chen, Anthi Chatzikyriakidou, Christina Keskini, Theofanis Pappas, Eleftherios Anastasopoulos, Alexandros Lambropoulos, Evangelia S. Panagiotou, Dimitrios G. Mikropoulos, Ewa Kosior-Jarecka, Augustine Cheong, Yuanhan Li, Urszula Lukasik, Monisha E. Nongpiur, Rahat Husain, Shamira A. Perera, Lydia Álvarez, Montserrat García, Héctor González-Iglesias, Andrés Fernández-Vega Cueto, Luis Fernández-Vega Cueto, Federico Martinón-Torres, Antonio Salas, Çilingir Oguz, Nevbahar Tamcelik, Eray Atalay, Bilge Batu, Murat Irkec, Dilek Aktas, Burcu Kasim, Yury S. Astakhov, Sergei Y. Astakhov, Eugeny L. Akopov, Andreas Giessl, Christian Mardin, Claus Hellerbrand, Jessica N. Cooke Bailey, Robert P. Igo, Jonathan L. Haines, Deepak P. Edward, Steffen Heegaard, Sonia Davila, Patrick Tan, Jae H. Kang, Louis R. Pasquale, Friedrich E. Kruse, André Reis, Trevor R. Carmichael, Michael Hauser, Michele Ramsay, Georg Mossböck, Nilgun Yildirim, Kei Tashiro, Anastasios G. P. Konstas, Miguel Coca-Prados, Jia Nee Foo, Shigeru Kinoshita, Chie Sotozono, Toshiaki Kubota, Michael Dubina, Robert Ritch, Janey L. Wiggs, Francesca Pasutto, Ursula Schlötzer-Schrehardt, Ying Swan Ho, Tin Aung, Wai Leong Tam, Chiea Chuen Khor. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye. JAMA, 2021; 325 (8): 753 DOI: 10.1001/jama.2021.0507
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