Mutant RAMP2 causes primary openl-angle glaucoma via the CRLR-cAMP axis
Mutant RAMP2 causes primary openl-angle glaucoma via the CRLR-cAMP axis
复制标题
RAMP2突变通过CRLR-cAMP轴引起原发性开角型青光眼
DOI：
10.1038/s41436-019-0507-0
复制
发表时间：
2019-10-01
影响因子：
8.8
通讯作者：
Yang, Zhenglin
中科院分区：
文献类型：
--
作者：
Gong, Bo;Zhang, Houbin;Yang, Zhenglin
目的：原发性开角型青光眼（POAG）是全球不可逆性失明的主要原因，已知基因的突变仅能解释5 - 6%的POAG病例。本研究旨在鉴定新的致POAG基因，并探索该疾病的发病机制。
方法：对一个包含398例散发POAG病例的汉族人群队列和2010例对照进行外显子组测序，随后通过桑格测序进行验证研究。构建了杂合的Ramp2基因敲除小鼠模型用于体内功能研究。
结果：通过外显子组测序分析和验证研究，我们在三个遗传多样性的人群（汉族、德国人和印度人）中鉴定出受体活性修饰蛋白2（RAMP2）的致病变异。在4763例POAG患者中的16例中鉴定出6种杂合的RAMP2致病变异（Glu39Asp、Glu54Lys、Phe103Ser、Asn113Lysfs*10、Glu143Lys和Ser171Arg），而在10953例对照个体的RAMP2任何外显子中均未检测到变异。突变的RAMP2在转染细胞中聚集，并导致AMRAMP2/CRLR - cAMP信号通路受损。在小鼠中，一个Ramp2等位基因的缺失导致cAMP减少和视网膜神经节细胞死亡。
结论：本研究表明RAMP2/CRLR - cAMP轴的破坏可导致POAG，并确定了一种针对POAG的潜在治疗干预措施。
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 AMRAMP2/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.