Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis

Journal article

Publication Details

Author(s): Gong B, Zhang H, Huang L, Chen Y, Shi Y, Tam POS, Zhu X, Huang Y, Lei B, Sundaresan P, Li X, Jiang L, Yang J, Lin Y, Lu F, Chen L, Li Y, Leung CKS, Guo X, Zhang S, Huang G, Wu Y, Zhou T, Shuai P, Tham CCY, Weisschuh N, Krishnadas SR, Mardin C, Reis A, Yang J, Zhang L, Zhou Y, Wang Z, Qu C, Shaw PX, Pang CP, Sun X, Zhu W, Li DY, Pasutto F, Yang Z
Journal: Genetics in Medicine
Publication year: 2019
ISSN: 1098-3600


Purpose: 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. Methods: 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. Results: 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. Conclusion: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.

External institutions with authors

Aravind Medical Research Foundation
Eberhard Karls Universität Tübingen
Fudan University / 复旦大学
The Chinese University of Hong Kong (CUHK)
University of California, San Diego
University of Electronic Science and Technology of China (UESTC) / 电子科技大学
University of Utah
Zhengzhou University / 郑州大学

How to cite

Gong, B., Zhang, H., Huang, L., Chen, Y., Shi, Y., Tam, P.O.S.,... Yang, Z. (2019). Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis. Genetics in Medicine.

Gong, Bo, et al. "Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis." Genetics in Medicine (2019).


Last updated on 2019-29-05 at 14:23