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Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease. Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice. This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.


Bo Gong, Houbin Zhang, Lulin Huang, Yuhong Chen, Yi Shi, Pancy Oi-Sin Tam, Xianjun Zhu, Yi Huang, Bo Lei, Periasamy Sundaresan, Xi Li, Linxin Jiang, Jialiang Yang, Ying Lin, Fang Lu, Lijia Chen, Yuanfeng Li, Christopher Kai-Shun Leung, Xiaoxin Guo, Shanshan Zhang, Guo Huang, Yaqi Wu, Tongdan Zhou, Ping Shuai, Clement Chee-Yung Tham, Nicole Weisschuh, Subbaiah Ramasamy Krishnadas, Christian Mardin, André Reis, Jiyun Yang, Lin Zhang, Yu Zhou, Ziyan Wang, Chao Qu, Peter X Shaw, Chi-Pui Pang, Xinghuai Sun, Weiquan Zhu, Dean Yaw Li, Francesca Pasutto, Zhenglin Yang. Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis. Genetics in medicine : official journal of the American College of Medical Genetics. 2019 Oct;21(10):2345-2354

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PMID: 31000793

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