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1. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author

Ekaterina Yonova-Doing, Wanting Zhao, Robert P. Igo, Chaolong Wang, Periasamy Sundaresan, Kristine E. Lee, Gyungah R. Jun, Alexessander Couto Alves, Xiaoran Chai, Anita S. Y. Chan, Mei Chin Lee, Allan Fong, Ava G. Tan, Chiea Chuen Khor, Emily Y. Chew, Pirro G. Hysi, Qiao Fan, Jacqueline Chua, Jaeyoon Chung, Jiemin Liao, Johanna M. Colijn, Kathryn P. Burdon, Lars G. Fritsche, Maria K. Swift, Maryam H. Hilmy, Miao Ling Chee, Milly Tedja, Pieter W. M. Bonnemaijer, Preeti Gupta, Queenie S. Tan, Zheng Li, Eranga N. Vithana, Ravilla D. Ravindran, Soon-Phaik Chee, Yuan Shi, Wenting Liu, Xinyi Su, Xueling Sim, Yang Shen, Ya Xing Wang, Hengtong Li, Yih-Chung Tham, Yik Ying Teo, Tin Aung, Kerrin S. Small, Paul Mitchell, Jost B. Jonas, Tien Yin Wong, Astrid E. Fletcher, Caroline C. W. Klaver, Barbara E. K. Klein, Jie Jin Wang, Sudha K. Iyengar, Christopher J. Hammond, and Ching-Yu Cheng

Subjects
Biology (General), QH301-705.5
Abstract

Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Published
2020
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2. Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Author

Preeti Gupta, Maryam Hazly Hilmy, Jie Jin Wang, Jiemin Liao, Allan Fong, Maria K. Swift, Johanna M. Colijn, Paul Mitchell, Ya Xing Wang, Anita S Y Chan, Barbara E.K. Klein, Pirro G. Hysi, Jaeyoon Chung, Emily Y. Chew, Wanting Zhao, Yang Shen, Ava Grace Tan, Hengtong Li, Eranga N. Vithana, Gyungah Jun, Wenting Liu, Tin Aung, Qiao Fan, Yuan Shi, Ekaterina Yonova-Doing, Soon-Phaik Chee, Sudha K. Iyengar, Yik Ying Teo, Periasamy Sundaresan, Chiea Chuen Khor, Zheng Li, Kathryn P. Burdon, Miao Ling Chee, Yih Chung Tham, Christopher J Hammond, Xiaoran Chai, Kerrin S. Small, Queenie S. Tan, Jacqueline Chua, Jost B. Jonas, Astrid E. Fletcher, Alexessander Couto Alves, Pieter W.M. Bonnemaijer, Ravilla D. Ravindran, Mei Chin Lee, Milly S. Tedja, Robert P. Igo, Kristine E. Lee, Tien Y Wong, Xinyi Su, Caroline C W Klaver, Xueling Sim, Ching-Yu Cheng, Chaolong Wang, Lars G. Fritsche, Epidemiology, and Ophthalmology

Subjects
0301 basic medicine, Genotype, genetic structures, QH301-705.5, Medicine (miscellaneous), Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Genome-wide association studies, Cataract, Article, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, Allele, Biology (General), Alleles, Genetic Association Studies, Genetic association, business.industry, SOXB1 Transcription Factors, Genetic Variation, medicine.disease, eye diseases, 030104 developmental biology, Age-related nuclear cataract, 030221 ophthalmology & optometry, Congenital cataracts, Lens diseases, sense organs, General Agricultural and Biological Sciences, business, Genome-Wide Association Study
Abstract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Published
2020

3. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. K, Khan, Muhammad Imran, Olawoye, Olusola O, Ashaye, Adeyinka O, Ugbede, Idakwo, Onakoya, Adeola, Kizor Akaraiwe, Nkiru, Teekhasaenee, Chaiwat, Suwan, Yanin, Supakontanasan, Wasu, Okeke, Suhanya, Uche, Nkechi J, Asimadu, Ifeoma, Ayub, Humaira, Akhtar, Farah, Kosior Jarecka, Ewa, Lukasik, Urszula, Lischinsky, Ignacio, Castro, Vania, Grossmann, Rodolfo Perez, Megevand, Gordana Sunaric, Roy, Sylvain, Dervan, Edward, Silke, Eoin, Rao, Aparna, Sahay, Priti, Fornero, Pablo, Cuello, Osvaldo, Sivori, Delia, Zompa, Tamara, Mills, Richard A, Souzeau, Emmanuelle, Mitchell, Paul, Wang, Jie Jin, Hewitt, Alex W, Coote, Michael, Crowston, Jonathan G, Astakhov, Sergei Y, Akopov, Eugeny L, Emelyanov, Anton, Vysochinskaya, Vera, Kazakbaeva, Gyulli, Fayzrakhmanov, Rinat, Al Obeidan, Saleh A, Owaidhah, Ohoud, Aljasim, Leyla Ali, Chowbay, Balram, Foo, Jia Nee, Soh, Raphael Q, Sim, Kar Seng, Xie, Zhicheng, Cheong, Augustine W. O, Mok, Shi Qi, Soo, Hui Meng, Chen, Xiao Yin, Peh, Su Qin, Heng, Khai Koon, Husain, Rahat, Ho, Su Ling, Hillmer, Axel M, Cheng, Ching Yu, Escudero Domínguez, Francisco A, González Sarmiento, Rogelio, Martinon Torres, Frederico, Salas, Antonio, Pathanapitoon, Kessara, Hansapinyo, Linda, Wanichwecharugruang, Boonsong, Kitnarong, Nari, Sakuntabhai, Anavaj, Nguyn, Hip X, Nguyn, Giang T. T, Nguyn, Trình V, Zenz, Werner, Binder, Alexander, Klobassa, Daniela S, Hibberd, Martin L, Davila, Sonia, Herms, Stefan, Nöthen, Markus M, Moebus, Susanne, Rautenbach, Robyn M, Ziskind, Ari, Carmichael, Trevor R, Ramsay, Michele, Álvarez, Lydia, García, Montserrat, González Iglesias, Héctor, Rodríguez Calvo, Pedro P, Cueto, Luis Fernández Vega, Oguz, Çilingir, Tamcelik, Nevbahar, Atalay, Eray, Batu, Bilge, Aktas, Dilek, Kasım, Burcu, Wilson, M. Roy, Coleman, Anne L, Liu, Yutao, Challa, Pratap, Herndon, Leon, Kuchtey, Rachel W, Kuchtey, John, Curtin, Karen, Chaya, Craig J, Crandall, Alan, Zangwill, Linda M, Wong, Tien Yin, Nakano, Masakazu, Kinoshita, Shigeru, den Hollander, Anneke I, Vesti, Eija, Fingert, John H, Lee, Richard K, Sit, Arthur J, Shingleton, Bradford J, Wang, Ningli, Cusi, Daniele, Qamar, Raheel, Kraft, Peter, Pericak Vance, Margaret A, Raychaudhuri, Soumya, Heegaard, Steffen, Kivelä, Tero, Reis, André, Kruse, Friedrich E, Weinreb, Robert N, Pasquale, Louis R, Haines, Jonathan L, Thorsteinsdottir, Unnur, Jonasson, Fridbert, Allingham, R. Rand, Milea, Dan, Ritch, Robert, Kubota, Toshiaki, Tashiro, Kei, Vithana, Eranga N, Micheal, Shazia, Topouzis, Foti, Craig, Jamie E, Dubina, Michael, Sundaresan, Periasamy, Stefansson, Kari, Wiggs, Janey L, Pasutto, Francesca, Khor, Chiea Chuen, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and University of Helsinki

Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

4. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Author

Mineo Ozaki, Marcelo T. Nicolela, Theofanis Pappas, Fotis Topouzis, Andrés Fernández-Vega Cueto, Panayiota Founti, Eray Atalay, Nilgun Yildirim, Chie Sotozono, Christina Keskini, Yosai Mori, Luis Fernández-Vega Cueto, Andrew C. Orr, Murat Irkec, Yuanhan Li, Deepak P. Edward, Satoko Nakano, Yury S. Astakhov, Tsutomu Ohashi, Daniel Gaston, George Chichua, Evangelia S Panagiotou, Ursula Schlötzer-Schrehardt, Jae H. Kang, Sergo Tabagari, Federico Martinón-Torres, Akitoshi Yoshida, Lesya M. Shuba, Masaru Inatani, Ken Hayashi, Takako Sugimoto, Shamira A. Perera, Takanori Mizoguchi, Kar Seng Sim, Friedrich E. Kruse, Shin-ichi Manabe, Andreas Giessl, Joseph Saunders, Ewa Kosior-Jarecka, Christian Y. Mardin, Wai Leong Tam, Hui Meng Soo, Makoto Aihara, Yoshiaki Kiuchi, Tomomi Higashide, Wee Yang Meah, Rahat Husain, Tin Aung, Sergei Y. Astakhov, Zheng Li, Dimitrios G. Mikropoulos, André Reis, Eleftherios Anastasopoulos, Jessica N. Cooke Bailey, Anastasios G. P. Konstas, Toshiya Sakurai, Dilek Aktas, Montserrat García, Bilge Batu, Hideki Chuman, Shigeru Kinoshita, Matthias Zenkel, Ying Swan Ho, Nevbahar Tamçelik, Masakazu Nakano, Jonathan L. Haines, Nino Kobakhidze, Kazuhiko Mori, Esther Kai Lay Peh, Francesca Pasutto, Georg Mossböck, Anthi Chatzikyriakidou, Robert P. Igo, Etsuo Chihara, Kazuhisa Sugiyama, Janey L. Wiggs, Michael V. Dubina, Shuwen Chen, Paul E Rafuse, Xiao Yin Chen, Trevor R. Carmichael, Kei Tashiro, Miguel Coca-Prados, Claus Hellerbrand, Shigeyasu Kazama, Çilingir Oguz, Alexandros Lambropoulos, Patrick Tan, Michael A. Hauser, Burcu Kasım, Michèle Ramsay, Morio Ueno, Kana Tokumo, Kenji Inoue, Robert Ritch, Tomasz Zarnowski, Toshiaki Kubota, Sonia Davila, Steffen Heegaard, Ryuichi Ideta, Lydia Álvarez, Yoko Ikeda, Chiea Chuen Khor, Susan Williams, Satoshi Ishiko, Louis R. Pasquale, Eugeny L. Akopov, Antonio Salas, Alina Popa-Cherecheanu, Monisha E. Nongpiur, Héctor González-Iglesias, Urszula Lukasik, Jia Nee Foo, Augustine Cheong, Zhenxun Wang, Mei Chin Lee, Anita Chan, and Kazunori Miyata

Subjects
Risk, Loxl1, medicine.medical_specialty, Glaucoma, Gene, 01 natural sciences, Exfoliation syndrome, 03 medical and health sciences, Low-Frequency, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Disease, 030212 general & internal medicine, 0101 mathematics, Exfoliation (botany), Exome sequencing, Original Investigation, business.industry, Protein, 010102 general mathematics, Case-control study, General Medicine, Odds ratio, medicine.disease, Pseudoexfoliation Syndrome, Susceptibility, Cohort, business
Abstract

IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

Published
2021

5. Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function

Author

Maryam Hazly Hilmy, Eranga N. Vithana, Boon-Tin Chua, Mei Chin Lee, Mani Baskaran, Chiea Chuen Khor, Tin Aung, Monisha E. Nongpiur, Walter Hunziker, Yaan-Fun Chong, Anita S Chan, Shuang-Ru Goh, and William Shei

Subjects
0301 basic medicine, rac1 GTP-Binding Protein, RHOA, Blood-Aqueous Barrier, Iris, RAC1, Cell junction, Polymorphism, Single Nucleotide, Actin cytoskeleton organization, Tight Junctions, 03 medical and health sciences, Cell Movement, Genetics, medicine, Humans, Genetic Predisposition to Disease, cdc42 GTP-Binding Protein, Molecular Biology, Genetics (clinical), biology, Tight junction, Epithelial Cells, General Medicine, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Intercellular Junctions, Cdc42 GTP-Binding Protein, biology.protein, Trabecular meshwork, Carrier Proteins, Glaucoma, Angle-Closure
Abstract

PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with the C risk allele of the sentinel SNP rs11024102 with the risk allele carrier groups having significantly reduced PLEKHA7 levels compared to non-risk allele carriers. Silencing of PLEKHA7 in human immortalized non-pigmented ciliary epithelium (h-iNPCE) and primary trabecular meshwork cells, which are intimately linked to BAB and aqueous humor outflow respectively, affected actin cytoskeleton organization. PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42, but not RhoA, and the activation status of the two small GTPases is linked to PLEKHA7 expression levels. PLEKHA7 stimulates Rac1 and Cdc42 GTP hydrolysis, without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP. Consistent with the regulatory role of Rac1 and Cdc42 in maintaining the tight junction permeability, silencing of PLEKHA7 compromises the paracellular barrier between h-iNPCE cells. Thus, downregulation of PLEKHA7 in PACG may affect BAB integrity and aqueous humor outflow via its Rac1/Cdc42 GAP activity, thereby contributing to disease etiology.

Published
2017

6. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

Author

Tina T. Wong, Yaan Fun Chong, Kathryn P. Burdon, Sancy Low, Ningli Wang, Tuan Anh Tran, Emma Rusmayani, Alexander C Day, Kei Tashiro, Tam Thi Luu, Aye Thi Han, Christine A. Kiire, Nay Lin Oo, Hiroshi Sakai, Ewa Kosior-Jarecka, Sripriya Sarangapani, Mimiwati Zahari, Widya Artini Wiyogo, Seng-Chee Loon, Rigo Daniel Reyes, Rrima Dada, Robert Ritch, E-Shyong Tai, Jin-Xin Bei, Ren-Yi Wu, Balekudaru Shantha, Leyla Al-Jasim, Giulia Consolandi, Ya Xing Wang, Saleh A. Al-Obeidan, Tomasz Zarnowski, Shazia Micheal, Maria Luisa Guevara-Fujita, Raquel Quino, Yuzhen Jiang, Monisha E. Nongpiur, Yik Y. Teo, Francesca Pasutto, Hailin Meng, Mani Baskaran, Shigeru Kinoshita, Sunee Chansangpetch, Clement C Y Tham, Eranga N. Vithana, Paul J. Foster, Greet J. Boland, Deepak P. Edward, Young Hoon Hwang, Daniel H. Su, Ricardo Fujita, Huan Nguyen Pham, Yong Ho Sohn, Mark Seielstad, Rengaraj Venkatesh, Paul Mitchell, Morio Ueno, Chaw Chaw Khaing, Thanh Thu Nguyen, Celso Tello, Anita S. Chan, Muhammad Imran Khan, Vernon Yong, Eileen Png, Takanori Mizoguchi, Nguyen Van Vinh Chau, Soo Hong Chew, Laura Dallorto, Chunyan Qiao, Donald T.H. Tan, Norlina Ramli, Mei Chin Lee, Rahat Husain, Kar Seng Sim, Sarah J. Dunstan, Kyu Hyung Park, Stephen A Vernon, Thi Nguyen, Rodolfo A. Perez-Grossmann, Jelinar Mohamed-Noor, Jeeyun Ahn, David Lozano-Giral, Tan Do, Yin Mon Aung, Prin Rojanapongpun, Naris Kitnarong, Martin L. Hibberd, Chan-Yun Kim, Mineo Ozaki, Manchima Makornwattana, Ronnie George, José Paulo Cabral de Vasconcellos, Huong T T Bui, Chona S Liao, Saw Htoo Set, Chi Pui Pang, Paul T K Chew, Aliza Jap, Naushin Waseem, Toshiaki Kubota, Tanuj Dada, Hyoung Won Bae, Tin Aung, Ricardo Y. Abe, Khin Thida Oo, Periasamy Sundaresan, Jose Maria Martinez, Visanee Tantisevi, Shomi S. Bhattacharya, Anneke I. den Hollander, Vira Wardhana Istiantoro, Rohit Shetty, Boonsong Wanichwecharungruang, Liang Xu, Seng Kheong Fang, Masakazu Nakano, E. Randy Craven, Richard P. Ebstein, Ching-Lin Ho, Arkasubhra Ghosh, Jeanne J. Ogle, Hongyan Jia, Muneeb A. Faiq, Yasuo Kurimoto, Michiko Yonahara, Richard Stead, Li Jia Chen, Satoko Nakano, Anavaj Sakuntabhai, Masako Kuroda, Thayanithi Sandragasu, Leonard W. Yip, Lerprat Mangkornkanokpong, Pancy O. S. Tam, Seang-Mei Saw, Ching-Yu Cheng, Saravanan Vijayan, Jia Nee Foo, M B Melo, Wing Lau Ho, Ahmad Tajudin Liza-Sharmini, Alex W. Hewitt, Mary Ann T Catacutan, Carlo Lavia, Curt Hartleben-Matkin, Hon-Tym Wong, Daniela Paoli, Srinivasan Kavitha, Su Nyunt Zaw, Soon Thye Lim, Owen Hee, Yee Yee Aung, Shuang Ru Goh, Chiea Chuen Khor, Maria Cecilia Aquino, Jonathan C.H. Chan, Buddha Basnyat, Zeiras Eka Djamal, Nhu Hon Do, Tuyet Bach Trinh, John H. Fingert, Z. Xie, Thi Lam Huong Dao, Urszula Lukasik, Bruno Batista de Souza, Khaled K. Abu-Amero, Yoko Ikeda, Guillermo Barreto Fong, Eng Hui Gan, Guangxian Tang, Sami Al-Shahwan, Tien Dat Tran, Jost B. Jonas, Xiao Yin Chen, Nagaswamy Soumittra, David Goh, Ramanjit Sihota, Xiao-Yu Ng, Ki Ho Park, Mona S Awadalla, Sujie Fan, Edgar U Leuenberger, Hlaing May Than, Jimmy S. M. Lai, Yi Xin Zeng, Shamira A. Perera, Bonnie Nga Kwan Choy, Jie Jin Wang, Roopam Duvesh, Antonio Maria Fea, Anita Manassakorn, Victor H. K. Yong, Abhilasha Karkey, John F Salmon, Kessara Pathanapitoon, Raheel Qamar, Juan Carlos Zenteno, Jin Wook Jeoung, Jovell Ian M Peregrino, Harm Snippe, Yaakub Azhany, Humaira Ayub, Vania Castro Tamanaja, Paolo Frezzotti, Tung S Hoan, Rajesh S. Kumar, Chelvin C A Sng, Jamie E Craig, Anuwat Prutthipongsit, Vital Paulino Costa, Subbiah. R. Krishnadas, Kuldeep Mohanty, Michael A. Hauser, Vi Huyen Doan, Irene R Felarca, Lingam Vijaya, Jennifer W. H. Shum, Farah Akhtar, R. Rand Allingham, Nuttamon Srisamran, Desmond Quek, Huaizhou Wang, Thipnapa Patthanathamrongkasem, Giulia Pignata, Suman S Thapa, Kazuhiko Mori, Jamil Miguel Neto, Tien Yin Wong, Boon-Ang Lim, Zheng Li, Genome Institute of Singapore (GIS), National University of Singapore (NUS), Vietnam National Institute of Ophthalmology (VNIO), Beijing Tongren Hospital, Kyoto University [Kyoto], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This research is supported by the Singapore Ministry of Health's National Medical Research Council under its Translational and Clinical Research (TCR) Flagship Programme Grant Stratified Medicine for Primary Angle Closure Glaucoma (NMRC/TCR/008-SERI/2013) and the Singapore Translational Research (STaR) Investigator Award Singapore Angle Closure Glaucoma Program Characterization, Prevention, and Management (NMRC/STAR/0023/2014), as well as the Biomedical Research Council, Agency for Science, Technology and Research (A-STAR), Singapore. A.T.L.-S. gratefully acknowledges support from grants RUI 1001/PPSP/812101 and RUI 1001/PPSP/812152 from the Universiti Sains Malaysia. H.J., C.Q., and N. Wang acknowledge support from the Program of Beijing Scholars (2013), Leading Talents–High-Level Talents of the Health System of Beijing (2009-1-05), and the National Major Scientific and Technological Special Project for 'Significant New Drugs Development' (2011ZX09302-007-05), as well as Project of the National Natural Science Foundation of China (81570837) grants., Kyoto University, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, MESH: Gene Expression, Genotype, Population, Gene Expression, Glaucoma, Genome-wide association study, Biology, Primary angle-closure glaucoma, MESH: Genetic Loci, Cell Line, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, education, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Genetic Predisposition to Disease, Chromosome Mapping, Odds ratio, medicine.disease, MESH: Male, 3. Good health, MESH: Cell Line, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, 030221 ophthalmology & optometry, Susceptibility locus, MESH: Glaucoma, Angle-Closure, Female, Glaucoma, Angle-Closure, MESH: Chromosome Mapping, MESH: Female, Genome-Wide Association Study
Abstract

International audience; Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Published
2016

7. Chelerythrine and Sanguinarine Dock at Distinct Sites on BclXL that are Not the Classic BH3 Binding Cleft

Author

Kah Fei Wan, Anirban Bhunia, Mei Chin Lee, Shing Leng Chan, Yonghong Zhang, Yu-Keung Mok, and Victor C. Yu

Subjects
Models, Molecular, Protein family, Amino Acid Motifs, Molecular Conformation, bcl-X Protein, Antineoplastic Agents, Apoptosis, chemistry.chemical_compound, Alkaloids, BH3 peptide, Structural Biology, Cell Line, Tumor, DOCK, Humans, Sanguinarine, Nuclear Magnetic Resonance, Biomolecular, Molecular Biology, Benzophenanthridines, Binding Sites, Chemistry, Isoquinolines, Cell biology, Chelerythrine, Biochemistry, Docking (molecular), Mutagenesis, Site-Directed, biological phenomena, cell phenomena, and immunity, Epitope Mapping, Heteronuclear single quantum coherence spectroscopy
Abstract

The ratio of the levels of pro-survival and pro-apoptotic members of the Bcl-2 protein family is thought to be an important regulatory factor for determining the sensitivity of the mammalian cells to apoptotic stimuli. High levels of expression of pro-survival members such as Bcl(XL) in human cancers were frequently found to be a good prognostic indicator predicting poor response to chemotherapy. The pro-survival members of the Bcl-2 family mediate their effects through heterodimerization with the BH3 region of the pro-apoptotic members. Structural analyses of the binding complex of the BH3 peptide and Bcl(XL) showed that a hydrophobic groove termed the BH3 binding cleft is the docking site for the BH3 region. Chemical mimetics of the BH3 region such as BH3I-1 that target the BH3 binding cleft indeed exhibit pro-apoptotic activities. Chelerythrine (CHE) and sanguinarine (SAN) are natural benzophenanthridine alkaloids that are structurally homologous to each other. CHE was previously identified as an inhibitor of Bcl(XL) function from a high-throughput screen of natural products, but its mode of interaction with Bcl(XL) is not known. By determining the effect of site-directed mutagenesis on ligand binding and using saturation transfer difference (STD) NMR experiments, we have verified locations of these docked ligands. Surprisingly, CHE and SAN bind separately at the BH groove and BH1 region of Bcl(XL) respectively, different from the BH3 binding cleft where other known inhibitors of Bcl(XL) target. Interestingly, certain residues on the flexible loop between helices alpha1 and alpha2 of Bcl(XL) are also perturbed upon CHE, but not SAN or BH3I-1 binding. Although CHE and SAN are similarly effective as BH3I-1 in displacing bound BH3 peptide, they are much more effective in inducing apoptosis, raising the possibility that CHE and SAN might be able to antagonize other pro-survival mechanisms in addition to the one that involves BH3 region binding.

Published
2006

8. A common variant near TGFBR3 is associated with primary open angle glaucoma

Author

Zhenglin Yang, Tien Yin Wong, Zheng Li, Kei Tashiro, R. Rand Allingham, Julia E. Richards, Nobuo Fuse, Wee Yang Meah, Robert Ritch, Yik Ying Teo, Dan Milea, Takanori Mizoguchi, Puya Gharahkhani, David F. Garway-Heath, David Goh, Yoko Ikeda, Allison E. Ashley Koch, Wang Xu, Baskaran Mani, Ronnie George, Masakazu Nakano, Jessica N. Cooke Bailey, Janey L. Wiggs, Ying Lin, Yutao Liu, Xiao Yu Ng, Hong Zhang, Stuart MacGregor, Leon W. Herndon, Mei Chin Lee, Elaine Chua, Jost B. Jonas, Tran Nguyen Bich Chau, Balekudaru Shantha, Cameron P. Simmons, SR Krishnadas, Kazuhiko Mori, Ching-Lin Ho, Rupert R A Bourne, Augusto Azuara Blanco, Ching-Yu Cheng, Kathryn P. Burdon, Liza-Sharmini Ahmad Tajudin, Shamira A. Perera, Do Nhu Hon, Louis R. Pasquale, Monisha E. Nongpiur, Khaled K. Abu-Amero, Tin Aung, Rahat Husain, Anil Negi, Ningli Wang, Chukai Huang, Jinghong Sang, Mineo Ozaki, Sarangapani Sripriya, E-Shyong Tai, Saleh A. Al-Obeidan, Jong Chul Han, Chiea Chuen Khor, Jia Nee Foo, Mingzhi Zhang, David C Broadway, David A. Mackey, Ryuichi Sato, Songhomita Panda-Jonas, Prasanthi Namburi, Jamie E Craig, Merwyn Chew, Nihong Zhang, Christopher A. Girkin, Jae H. Kang, Blanche Lim, Anita S Y Chan, Yuhong Chen, Michael A. Hauser, Douglas E. Gaasterland, Chi Pui Pang, Daniel H. Su, Pascal Reynier, Azhany Yakub, Pratap Challa, Alex W. Hewitt, Bowen Zhao, Victor H. K. Yong, Saravanan Vijayan, Yi Xin Zeng, Jonathan L. Haines, Essam A. Osman, Pansy O.S. Tam, Lingam Vijaya, Xinghuai Sun, Aurelien Goncalves, Jianjun Liu, Morio Ueno, Sayoko E. Moroi, Shigeru Kinoshita, Liyun Jia, Kengo Yoshii, Seang-Mei Saw, Tina T. Wong, Yaan Fun Chong, Philomenadin Ferdinamarie Sharmila, Changwon Kee, Tan Do, Periasamy Sundaresan, Jin-Xin Bei, Eranga N. Vithana, Christopher Kai-shun Leung, Sohn Seongsoo, and Li Jia Chen

Subjects
Male, Open angle glaucoma, genetic structures, Genotype, Population, Glaucoma, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, SNP, Humans, education, Molecular Biology, Exome, Genetics (clinical), Alleles, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, education.field_of_study, Association Studies Articles, Genetic Variation, General Medicine, Odds ratio, Middle Aged, medicine.disease, eye diseases, 3. Good health, 030221 ophthalmology & optometry, Female, Proteoglycans, sense organs, Receptors, Transforming Growth Factor beta, Glaucoma, Open-Angle
Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Published
2014

9. Identification of Chelerythrine as an Inhibitor of BclXL Function

Author

Antony D. Buss, Alex S. Y. Lee, Victor C. Yu, Doel D. Soejarto, Lay-Kien Yang, Shing Leng Chan, Mei Chin Lee, Mark S. Butler, Nai Yang Fu, Horst Flotow, and Kuan Onn Tan

Subjects
Programmed cell death, bcl-X Protein, Gene Expression, Antineoplastic Agents, Apoptosis, Cytochrome c Group, Biochemistry, chemistry.chemical_compound, Alkaloids, Bcl-2-associated X protein, Proto-Oncogene Proteins, Tumor Cells, Cultured, medicine, Humans, Staurosporine, Enzyme Inhibitors, Molecular Biology, Etoposide, Nucleic Acid Synthesis Inhibitors, bcl-2-Associated X Protein, Benzophenanthridines, biology, Cytochrome c, Molecular Mimicry, Bcl-2 family, Membrane Proteins, Cell Biology, Mitochondria, Phenanthridines, Cell biology, bcl-2 Homologous Antagonist-Killer Protein, Chelerythrine, Proto-Oncogene Proteins c-bcl-2, chemistry, biology.protein, Bcl-2 Homologous Antagonist-Killer Protein, Protein Binding, medicine.drug
Abstract

The identification of small molecule inhibitors of antiapoptotic Bcl-2 family members has opened up new therapeutic opportunities, while the vast diversity of chemical structures and biological activities of natural products are yet to be systematically exploited. Here we report the identification of chelerythrine as an inhibitor of BclXL-Bak Bcl-2 homology 3 (BH3) domain binding through a high throughput screening of 107,423 extracts derived from natural products. Chelerythrine inhibited the BclXL-Bak BH3 peptide binding with IC50 of 1.5 micro m and displaced Bax, a BH3-containing protein, from BclXL. Mammalian cells treated with chelerythrine underwent apoptosis with characteristic features that suggest involvement of the mitochondrial pathway. While staurosporine, H7, etoposide, and chelerythrine released cytochrome c from mitochondria in intact cells, only chelerythrine released cytochrome c from isolated mitochondria. Furthermore BclXL-overexpressing cells that were completely resistant to apoptotic stimuli used in this study remained sensitive to chelerythrine. Although chelerythrine is widely known as a protein kinase C inhibitor, the mechanism by which it mediates apoptosis remain controversial. Our data suggest that chelerythrine triggers apoptosis through a mechanism that involves direct targeting of Bcl-2 family proteins.

Published
2003

10. High thermal conductivity underfill study for fine pitch Cu pillar bump

Author

Chi-Tung Yeh, Mei-Chin Lee, Mu-Hsuan Chan, Mike Ma, Pai-Yuan Lee, Steve Chiu, Huei-Nuan Huang, and Chun-Tang Lin

Subjects
Thermal copper pillar bump, chemistry.chemical_compound, Materials science, Thermal conductivity, Silicon nitride, chemistry, Chip-scale package, Composite material, Dissipation, Die (integrated circuit), Flip chip, Thermal expansion
Abstract

Along with the die size of device become more and more small, fine pitch, fine gap and multi-stacking are the market mainstream which applied for high performance system in advance technology, su ch as 3D IC. Th erefore, h eat dissipation is must process for this kind of electronic device to avoid internal heating form device during operate. Un derfill (UF) is an important process in 3D stackin g flip chip package that major function is reducing stress from coefficient of thermal expansion (CTE) mismatch, also can isolate bump and protect it. In this study, two kinds of fillers are evaluated on the heat dissipation which one is Silica and the other is Alumina. In order to clarify the performance of the test results, adhesion test was performed by pudding model on the silicon nitride. In addition, UF filing and flowing capability was determined by scanning acoustic tomography (SAT). Thermometer was used to analysis heat dissipation for comparing the effect of different UF filler material.

Published
2013

11. Integration of the metabolic/redox state, histone gene switching, DNA replication and S-phase progression by moonlighting metabolic enzymes

Author

Mei Chin Lee, Hongpeng He, Lei Zheng, Li Ling Zheng, and Yan Luo

Subjects
Protein moonlighting, Cytoplasm, lcsh:Life, lcsh:QR1-502, HDAC, histone deacetylase, OCA-S, Oct-1 co-activator in the S-phase, Review Article, SLBP, stem–loop-binding protein, Biochemistry, lcsh:Microbiology, S Phase, Histones, Transcription (biology), Histone methylation, nm23, non-metastasis 23, chromosome, Glyceraldehyde 3-phosphate dehydrogenase, CDK, cyclin-dependent kinase, ATM, ataxia telangiectasia mutated, LDH, lactate dehydrogenase, GAPDH, Glyceraldehyde-3-Phosphate Dehydrogenases, H2B, histone 2B, DNA-Binding Proteins, RNAi, RNA interference, Histone, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, Histone methyltransferase, histone 2B, NPAT, nuclear protein, ataxia-telangiectasia locus, ATR, ataxia telangiectasia mutated- and Rad3-related, Oxidation-Reduction, DNA Replication, awd, abnormal wing disc, S-phase, dm, Drosophila melanogaster, MMC, mammalian metabolic cycle, Biophysics, Biology, S4, PIKK, phosphoinositide 3-kinase-related kinase, Histone H2A, Humans, DSB, double-strand break, Molecular Biology, Cell Nucleus, HAT, histone acetyl transferase, L-Lactate Dehydrogenase, DNA replication, Cell Biology, CBP, CREB (cAMP-response-element-binding protein)-binding protein, NAD, YMC, yeast metabolic cycle, lcsh:QH501-531, enzyme, biology.protein, Tip60, Tat (transactivator of transcription)-interactive protein 60 kDa, HU, hydroxyurea
Abstract

The concept of one-protein–multiple-function, i.e. moonlighting proteins, is an ever-expanding paradigm. We obtained compelling evidence that an array of ‘cytoplasmic’ metabolic enzymes can enter the nuclei to carry out moonlighting transcription functions; this phenomenon is conserved from Drosophila to humans. Of particular interest are the classical glycolytic enzymes GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and LDH (lactate dehydrogenase), which utilize NAD(H) as coenzymes and not only moonlight (in their nuclear forms) to regulate the transcription of S-phase-specific histone genes, but also act as metabolic/redox sensors that link histone gene switching to DNA replication and S-phase progression.

Published
2013

12. Processing TSV wafer with stealth dicing technology

Author

Jeng-Yuan Lai, Chen Wan-Ting, Ming-Hsien Yang, Mei-Chin Lee, and Chun-Tang Lin

Subjects
Die preparation, Engineering, Through-silicon via, Semiconductor device fabrication, business.industry, Electronic engineering, Optoelectronics, Wafer testing, Wafer, Wafer dicing, business, Wafer backgrinding, Wafer-level packaging
Abstract

Conventional wafer dicing technology used on one side RDL structure of normal wafer is performed by blade dicing. Nowadays, it applies to through silicon via (TSV) wafer with double side RDL structure which emerges to serve a wide range of 3DIC applications that demands higher levels of performance and heterogeneity integration. However, the phenomenon of severe back-side chipping (BSC) occurs on the bottom surface of the wafer because of its exclusive structure. BSC may cause yield loss when micro-cracks exceeds the seal ring and also results in circuit damage and reliability failure of package device. To develop a method of chipping-free dicing, currently, stealth dicing (SD) is the best way for chip separation and its another distinguished advantage over other dicing methods is the completed dry process. Nevertheless, because of the limitation due to laser dynamic focal point, the warpage of ultra thin wafer is a critical challenge for SD. In this paper, SD technology used on TSV wafer was proposed, for the purpose of resolving warpage issue and reducing BSC, two dicing methods were applied to this study. Following by the study, chipping-free dicing is accomplished and a smooth surface is obtained, and the study method that the flat modified layer is formed with better performance in warpage.

Published
2012

13. Detection of micro defects in 3dic packages by means of non-destructive 3D X-ray

Author

Mei-Chin Lee, Chun-Tang Lin, Jeng-Yuan Lai, Chen Wan-Ting, and Ming-Hsien Yang

Subjects
Microscope, Materials science, medicine.diagnostic_test, business.industry, Computed tomography, law.invention, Data acquisition, law, Non destructive, Nondestructive testing, Electronic engineering, medicine, Micro defects, Integrated circuit packaging, business, Projection (set theory)
Abstract

In semiconductor assembly, destructive cross-section observation is the mainstream of defects analysis method, the issues that are making destructive analytical methods to be changed are more tedious and time consuming, because it might cause higher risk of creating artifacts. Nevertheless, advanced 3D x-ray technology enables to substitute the destructive analysis and provides the non-destructive detection of defects in 3DIC packages. The key challenge in its general operation principle is data acquisition time. This paper reviews the x-ray computed tomography method (CT scan) for non-destructive micro defects in 3DIC packages. The results have proved that 2D x-ray imaging capabilities is limited and the comparison in 3D x-ray operation principle between microscope and projection based imaging capabilities at micrometer resolution is practiced as a fine method to possibly observe defect shape, size and distribution by conducting the virtual cross-section at desired location. Based on the provided details of defect analysis, 3D x-ray works as a good method to provide non-destructive detect for 3DIC package applications.

Published
2012

14. Drosophila Octamer Elements and Pdm-1 Dictate the Coordinated Transcription of Core Histone Genes*

Author

Ling-Ling Toh, Lai-Ping Yaw, Mei Chin Lee, and Yan Luo

Subjects
Transcriptional Activation, Transcription, Genetic, SAP30, Biology, Biochemistry, Models, Biological, S Phase, Histones, Mice, Histone H1, Histone H2A, Histone methylation, Histone code, Animals, Deoxyribonuclease I, Drosophila Proteins, Gene Regulation, Histone octamer, Molecular Biology, RNA, Double-Stranded, Genetics, Cell Nucleus, Homeodomain Proteins, Pioneer factor, Cell Biology, Flow Cytometry, Drosophila melanogaster, Histone methyltransferase, POU Domain Factors, RNA Interference
Abstract

We reveal a set of divergent octamer elements in Drosophila melanogaster (dm) core histone gene promoters. These elements recruit transcription factor POU-domain protein in D. melanogaster 1 (Pdm-1), which along with co-activator dmOct-1 coactivator in S-phase (dmOCA-S), activates transcription from at least the Drosophila histone 2B (dmH2B) and 4 (dmH4) promoters in a fashion similar to the transcription of mammalian histone 2B (H2B) gene activated by octamer binding transcription factor 1 (Oct-1) and Oct-1 coactivator in S-phase (OCA-S). The expression of core histone genes in both kingdoms is coordinated; however, although the expression of mammalian histone genes involves subtype-specific transcription factors and/or co-activator(s), the expression of Drosophila core histone genes is regulated by a common module (Pdm-1/dmOCA-S) in a directly coordinated manner. Finally, dmOCA-S is recruited to the Drosophila histone locus bodies in the S-phase, marking S-phase-specific transcription activation of core histone genes.

Published
2010

15. Chelerythrine induces apoptosis through a Bax/Bak-independent mitochondrial mechanism

Author

Victor C. Yu, Sunil K. Sukumaran, Kah Fei Wan, Shing Leng Chan, and Mei-Chin Lee

Subjects
Programmed cell death, Apoptosis, Biochemistry, Mitochondrial apoptosis-induced channel, Sensitivity and Specificity, chemistry.chemical_compound, Mice, Bcl-2-associated X protein, Animals, Inner mitochondrial membrane, Molecular Biology, Cells, Cultured, bcl-2-Associated X Protein, Benzophenanthridines, Membrane Potential, Mitochondrial, biology, Cytochrome c, Mechanisms of Signal Transduction, Cytochromes c, Cell Biology, Molecular biology, Cell biology, Mitochondria, Enzyme Activation, Chelerythrine, bcl-2 Homologous Antagonist-Killer Protein, chemistry, Mitochondrial permeability transition pore, Caspases, biology.protein, Cyclosporine, Bcl-2 Homologous Antagonist-Killer Protein
Abstract

Although murine embryonic fibroblasts (MEFs) with Bax or Bak deleted displayed no defect in apoptosis signaling, MEFs with Bax and Bak double knock-out (DKO) showed dramatic resistance to diverse apoptotic stimuli, suggesting that Bax and Bak are redundant but essential regulators for apoptosis signaling. Chelerythrine has recently been identified as a Bcl-xL inhibitor that is capable of triggering apoptosis via direct action on mitochondria. Here we report that in contrast to classic apoptotic stimuli, chelerythrine is fully competent in inducing apoptosis in the DKO MEFs. Wild-type and DKO MEFs are equally sensitive to chelerythrine-induced morphological and biochemical changes associated with apoptosis phenotype. Interestingly, chelerythrine-mediated release of cytochrome c is rapid and precedes Bax translocation and integration. Although the BH3 peptide of Bim is totally inactive in releasing cytochrome c from isolated mitochondria of DKO MEFs, chelerythrine maintains its potency and efficacy in inducing direct release of cytochrome c from these mitochondria. Furthermore, chelerythrine-mediated mitochondrial swelling and loss in mitochondrial membrane potential (ΔΨm) are inhibited by cyclosporine A, suggesting that mitochondrial permeability transition pore is involved in chelerythrine-induced apoptosis. Although certain apoptotic stimuli have been shown to elicit cytotoxic effect in the DKO MEFs through alternate death mechanisms, chelerythrine does not appear to engage necrotic or autophagic death mechanism to trigger cell death in the DKO MEFs. These results, thus, argue for the existence of an alternative Bax/Bak-independent apoptotic mechanism that involves cyclosporine A-sensitive mitochondrial membrane permeability.

Published
2008

16. Erratum: Corrigendum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Author

Markus M. Nöthen, Jonathan G Crowston, Kazunori Miyata, Norimoto Gotoh, Masahide Yanagi, Stefan Herms, Steffen Heegaard, Ursula Schloetzer-Schrehardt, Shamira A. Perera, Axel M. Hillmer, Masaru Inatani, Yufen Goh, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Yildirim Nilgün, Aravind Haripriya, Lulin Huang, Daniela Paoli, Douglas J Rhee, Paul Mitchell, Mei Chin Lee, Inna May-Bolchakova, Masahiro Miyake, Ignacio Lischinsky, Toshiya Sakurai, Nagahisa Yoshimura, Makoto Aihara, Zhenglin Yang, Michael V. Dubina, Yoko Ikeda, Xueyi Chen, Yury S. Astakhov, Nihong Zhang, Ningli Wang, Kenji Inoue, Rhys A. Fogarty, John H. Fingert, Simon W. M. John, Kathryn P. Burdon, Steffen Uebe, Paolo Frezzotti, Pratap Challa, Alex W. Hewitt, Vera Vysochinskaya, Liang Xu, Fabian Lerner, Eleftherios Anastasopoulos, Satoshi Ishiko, Panayiota Founti, Rangappa Ramakrishnan, Kazuhisa Sugiyama, Janey L. Wiggs, Elke Schaeffeler, Etsuo Chihara, Morio Ueno, Matthew A. Brown, Louis R. Pasquale, Kai Yee Toh, Jie Jin Wang, Anne L. Coleman, Kazuhiko Mori, Jae H. Kang, Ewa Kosior-Jarecka, Christian Y. Mardin, Evgeny L. Akopov, Matthias Schwab, Saravanan Vijayan, Fumihiko Matsuda, Leyla Al-Jasim, Ya Xing Wang, Ken Hayashi, Juan Carlos Zenteno, David A. Mackey, Rajesh Kumar, Jost B. Jonas, Jia Nee Foo, Fotis Topouzis, Eranga N. Vithana, Yaz Yetkin, Yosai Mori, Wee Yang Meah, Kar Seng Sim, Rohit Shetty, Shahin Yazdani, Yik Ying Teo, Francesca Pasutto, Takanori Mizoguchi, Rahat Husain, Akitoshi Yoshida, Mohammad Pakravan, Ching-Yu Cheng, Tin Aung, Kei Tashiro, Tien Yin Wong, Trevor R. Carmichael, André Reis, Peiquan Zhao, Periasamy Sundaresan, Wallace L.M. Alward, Shigeyasu Kazama, Susan Williams, Zheng Li, Anthoula Chatzikyriakidou, Sergei Y. Astakhov, Su Ling Ho, Patricio G. Schlottmann, Essam A. Osman, Bowen Zhao, Urszula Lukasik, Balram Chowbay, Afsaneh Naderi Beni, Arkasubhra Ghosh, Ulrich Christoph Welge-Luessen, Nicole Weisschuh, Susanne Moebus, Shin Ichi Manabe, Chiea Chuen Khor, Ohoud Owaidhah, Paul Leo, Yoshiaki Kiuchi, Tomomi Higashide, Alexandros Lambropoulos, Anita S Y Chan, Michael A. Hauser, R. Rand Allingham, Deepak P. Edward, Jeffrey M. Harder, Mineo Ozaki, Takako Sugimoto, Çilingir Oaiuz, Su Qin Peh, Saleh A. Al-Obeidan, Robyn M. Rautenbach, Shigeru Kinoshita, Dalia Guadarrama-Vallejo, Robert Ritch, M. Roy Wilson, Tomasz Zarnowski, Khaled K. Abu-Amero, Michae Coote, Jinghong Sang, Ryuichi Ideta, Masakazu Nakano, Kenji Yamashiro, Gareth R. Howell, Andrew C. Orr, Leen Abu Safieh, Jeffrey M. Liebmann, Satoko Nakano, Liyun Jia, Kalpana Narendran, Yutao Liu, Toshiaki Kubota, Jamie E Craig, Sami Al Shahwan, Mandy Krumbiegel, Qisheng You, Ari Ziskind, Hideki Chuman, Allison E. Ashley Koch, and Rangaraj Venkatesh

Subjects
Genetics, Medizin, Biology, Exfoliation syndrome
Abstract

Corrigendum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Published
2015

18. Expression of the Primary Angle Closure Glaucoma (PACG) Susceptibility GenePLEKHA7in Endothelial and Epithelial Cell Junctions in the Eye

Author

Mei Chin Lee, Tin Aung, Monisha E. Nongpiur, Walter Hunziker, Maryam Hazly Hilmy, Eranga N. Vithana, Anita S. Y. Chan, Shuang Ru Goh, and Wanjin Hong

Subjects
Pathology, medicine.medical_specialty, Iris, Glaucoma, Biology, Real-Time Polymerase Chain Reaction, Transfection, Ciliary processes, Ciliary body, medicine, Humans, Genetic Predisposition to Disease, Iris (anatomy), Fluorescent Antibody Technique, Indirect, Cells, Cultured, Microscopy, Confocal, Ciliary Body, Endothelial Cells, Epithelial Cells, Muscle, Smooth, Blood–ocular barrier, medicine.disease, Immunohistochemistry, Actins, Epithelium, Platelet Endothelial Cell Adhesion Molecule-1, Intercellular Junctions, medicine.anatomical_structure, Gene Expression Regulation, Zonula Occludens-1 Protein, sense organs, Choroid, Trabecular meshwork, Carrier Proteins, Glaucoma, Angle-Closure, Biomarkers, Plasmids
Abstract

PURPOSE The role of the recently identified primary angle closure glaucoma (PACG) susceptibility gene, pleckstrin homology domain containing, family A member 7 (PLEKHA7), in PACG is unknown. PLEKHA7 associates with apical junctional complexes (AJCs) and is thus implicated in paracellular fluid regulation. We aimed to determine PLEKHA7's localization in the eye and its association with AJCs to elucidate its potential role in PACG. METHODS Total RNA from ocular tissues was isolated and analyzed by real-time PCR. Frozen and paraffin-embedded human globes were sectioned and used for immunohistochemistry and immunofluorescence analysis. RESULTS Specific PLEKHA7 expression was found in the muscles, vascular endothelium, and epithelium of the iris, ciliary body and ciliary processes, trabecular meshwork (TM), and choroid. PLEKHA7 expression in musculature and vascular endothelium was confirmed with smooth muscle marker, SMA, and endothelium marker, PECAM-1, respectively. At the above sites, PLEKHA7 colocalization was seen with adherens junction markers (E-cadherin and β-catenin) and tight junction markers (ZO-1). CONCLUSIONS Specific localization of PLEKHA7 was found within PACG-related structures (iris, ciliary body, and choroid) and blood-aqueous barrier (BAB) structures (posterior iris epithelium, nonpigmented ciliary epithelium, iris and ciliary body microvasculature). The association of PLEKHA7 with AJCs in the eye suggests a potential role for PLEKHA7 in PACG via fluidic regulation. Novel expression of PLEKHA7 was also seen in the ocular smooth muscles and vascular endothelia.

Published
2014

19. Integration of the metabolic/redox state, histone gene switching, DNA replication and S-phase progression by moonlighting metabolic enzymes.

Author

Hongpeng HE, Mei-Chin LEE, Li-Ling ZHENG, Lei ZHENG, and Yan LUO

Subjects
*DNA replication, *METABOLISM, *OXIDATION-reduction reaction, *HISTONES, *GLYCERALDEHYDEPHOSPHATE dehydrogenase, *TRANSCRIPTION factors, *CYTOPLASM, *CHROMOSOMES
Abstract

The concept of one-protein-multiple-function, i.e. moonlighting proteins, is an ever-expanding paradigm. We obtained compelling evidence that an array of 'cytoplasmic' metabolic enzymes can enter the nuclei to carry out moonlighting transcription functions; this phenomenon is conserved from Drosophila to humans. Of particular interest are the classical glycolytic enzymes GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and LDH (lactate dehydrogenase), which utilize NAD(H) as coenzymes and not only moonlight (in their nuclear forms) to regulate the transcription of S-phase-specific histone genes, but also act as metabolic/redox sensors that link histone gene switching to DNA replication and S-phase progression. [ABSTRACT FROM AUTHOR]

Published
2013
Full Text
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20. Drosophila Octamer Elements and Pdm-1 Dictate the Coordinated Transcription of Core Histone Genes.

Author

Mei-Chin Lee, Ling-Ling Toh, Lai-Ping Yaw, and Yan Luo

Subjects
*DROSOPHILA, *TRANSCRIPTION factors, *PROTEINS, *LOCUS (Genetics), *FRUIT flies, *GENE expression
Abstract

We reveal a set of divergent octamer elements in Drosophila melanogaster (dm) core histone gene promoters. These elements recruit transcription factor POU-domain protein in D. melanogaster 1 (Pdm-i), which along with co-activator dm~ct-1 coactivator in S-phase (dmOCA-S), activates transcription from at least the Drosophila histone 2B (dmH2B) and 4 (dml-14) promoters in a fashion similar to the transcription of mammalian histone 2B (H2B) gene activated by octamer binding transcription factor 1 (Oct-1) and Oct-1 coactivator in S-phase (OCA-S). The expression of core histone genes in both kingdoms is coordinated; however, although the expression of mammalian histone genes involves subtype-specific transcription factors and/or co-activator(s), the expression of Drosophila core histone genes is regulated by a common module (Pdm-1/dmOCA-S) in a directly coordinated manner. Finally, dmOCA-S is recruited to the Drosophila histone locus bodies in the S-phase, marking S-phase-specific transcription activation of core histone genes. [ABSTRACT FROM AUTHOR]

Published
2010
Full Text
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21. Identification of Chelerythrine as an Inhibitor of BclXL Function.

Author

Shing-Leng Chan, Mei Chin Lee, Kuan Onn Tan, Lay-Kien Yang, Lee, Alex S.Y., Flotow, Horst, Nai Yang Fu, Butler, Mark S., Soejarto, Doel D., Buss, Antony D., and Yu, Victor C.

Subjects
*BINDING sites, *APOPTOSIS
Abstract

Reports on the identification of chelerythrine as an inhibitor of BclXL-Bak Bcl-2 homology 3 domain binding through a high throughput screening of extracts derived from natural products. Observation on chelerythrine's ability in disrupting the interaction between BclXL and Bax peptide.

Published
2003
Full Text
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22. Processing TSV wafer with stealth dicing technology.

Author

Wan-Ting Chen, Mei-Chin Lee, Chun-Tang Lin, Ming-Hsien Yang, and Jeng-Yuan Lai

Abstract

Conventional wafer dicing technology used on one side RDL structure of normal wafer is performed by blade dicing. Nowadays, it applies to through silicon via (TSV) wafer with double side RDL structure which emerges to serve a wide range of 3DIC applications that demands higher levels of performance and heterogeneity integration. However, the phenomenon of severe back-side chipping (BSC) occurs on the bottom surface of the wafer because of its exclusive structure. BSC may cause yield loss when micro-cracks exceeds the seal ring and also results in circuit damage and reliability failure of package device. To develop a method of chipping-free dicing, currently, stealth dicing (SD) is the best way for chip separation and its another distinguished advantage over other dicing methods is the completed dry process. Nevertheless, because of the limitation due to laser dynamic focal point, the warpage of ultra thin wafer is a critical challenge for SD. In this paper, SD technology used on TSV wafer was proposed, for the purpose of resolving warpage issue and reducing BSC, two dicing methods were applied to this study. Following by the study, chipping-free dicing is accomplished and a smooth surface is obtained, and the study method that the flat modified layer is formed with better performance in warpage. [ABSTRACT FROM PUBLISHER]

Published
2012
Full Text
View/download PDF

23. Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains

Author

Li Hui Goh, Mei Chin Lee, Xiu Zhou, Yan Luo, Shuping Lin, Huashan Wang, and Xiaohang Yang

Subjects
Male, animal structures, lgl tumorigenesis suppression, Cell division, Neurogenesis, Ubiquitin-Protein Ligases, Parkinson's disease, Cell Cycle Proteins, Cell fate determination, Biology, Gene Expression Regulation, Enzymologic, Parkin, Neuroblast, Enzyme Stability, Asymmetric cell division, Animals, Drosophila Proteins, Molecular Biology, Protein Kinase C, Genetics, Drosophila neuroblast asymmetric division, Tumor Suppressor Proteins, Asymmetric Cell Division, fungi, Intracellular Signaling Peptides and Proteins, Brain, Gene Expression Regulation, Developmental, Nuclear Proteins, Neurodegenerative Diseases, Organ Size, Cell Biology, Neural stem cell, Cell biology, Enzyme Activation, Juvenile Hormones, Drosophila melanogaster, Larva, NUMB, Female, Gene Deletion, Protein Binding, Developmental Biology
Abstract

Asymmetric cell division of Drosophila neural stem cells or neuroblasts is an important process which gives rise to two different daughter cells, one of which is the stem cell itself and the other, a committed or differentiated daughter cell. During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. We identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. It preferentially binds to the aPKC/Bazooka/Partition Defective 6 complex and stabilizes aPKC levels. In clu mutants, Miranda (Mira) and Numb are mislocalized in small percentages of dividing neuroblasts. Adult mutants are short-lived with severe locomotion defects. Clu promotes tumorigenesis caused by loss of function of lethal(2) giant larvae (lgl) in the larval brain. Removal of clu in lgl mutants rescues Mira and Numb mislocalization and restores the enlarged brain size. Western blot analyses indicate that the rescue is due to the down-regulation of aPKC levels in the lgl clu double mutant. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. Our study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.

Full Text
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24. Chelerythrine Induces Apoptosis through a Bax/Bak-independent Mitochondrial Mechanism.

Author

Kah Fei Wan, Shing-Leng Chan, Sukumaran, Sunil Kumar, Mei-Chin Lee, and Yu, Victor C.

Subjects
*APOPTOSIS, *CELL death, *MITOCHONDRIA, *CYTOCHROMES, *MITOCHONDRIAL membranes, *CYCLOSPORINE
Abstract

Although murine embryonic fibroblasts (MEFs) with Bax or Bak deleted displayed no defect in apoptosis signaling, MEFs with Bax and Bak double knock-out (DKO) showed dramatic resistance to diverse apoptotic stimuli, suggesting that Bax and Bak are redundant but essential regulators for apoptosis signaling. Chelerythrine has recently been identified as a Bcl-xL inhibitor that is capable of triggering apoptosis via direct action on mitochondria. Here we report that in contrast to classic apoptotic stimuli, chelerythrine is fully competent in inducing apoptosis in the DKO MEFs. Wild-type and DKO MEFs are equally sensitive to chelerythrine-induced morphological and biochemical changes associated with apoptosis phenotype. Interestingly, chelerythrine-mediated release of cytochrome c is rapid and precedes Bax translocation and integration. Although the BH3 peptide of Bim is totally inactive in releasing cytochrome c from isolated mitochondria of DKO MEFs, chelerythrine maintains its potency and efficacy in inducing direct release of cytochrome c from these mitochondria. Furthermore, chelerythrine-mediated mitochondrial swelling and loss in mitochondrial membrane potential (ΔΨm) are inhibited by cyclosporine A, suggesting that mitochondrial permeability transition pore is involved in chelerythrine-induced apoptosis. Although certain apoptotic stimuli have been shown to elicit cytotoxic effect in the DKO MEFs through alternate death mechanisms, chelerythrine does not appear to engage necrotic or autophagic death mechanism to trigger cell death in the DKO MEFs. These results, thus, argue for the existence of an alternative Bax/Bak-independent apoptotic mechanism that involves cyclosporine A-sensitive mitochondrial membrane permeability. [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
View/download PDF

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