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