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Mutant RAMP2 Causes Primary Open-Angle Glaucoma Via the CRLR-Camp Axis

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Mutant RAMP2 Causes Primary Open-Angle Glaucoma Via the CRLR-Camp Axis © American College of Medical Genetics and Genomics ARTICLE Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis Bo Gong, PhD1,2, Houbin Zhang, PhD1, Lulin Huang, PhD1, Yuhong Chen, MD3, Yi Shi, PhD1, Pancy Oi-Sin Tam, MS4, Xianjun Zhu, PhD1, Yi Huang, MD1,5, Bo Lei, PhD6, Periasamy Sundaresan, PhD7, Xi Li, MS1, Linxin Jiang, MS1, Jialiang Yang, MS1, Ying Lin, MS1, Fang Lu, PhD1, Lijia Chen, MRCSEd (Ophth), PhD4, Yuanfeng Li, MS1, Christopher Kai-Shun Leung, MD4, Xiaoxin Guo, MS1, Shanshan Zhang, MS1, Guo Huang, MS1, Yaqi Wu, MS1, Tongdan Zhou, MS1, Ping Shuai, PhD1, Clement Chee-Yung Tham, FRCOphth4, Nicole Weisschuh, PhD8, Subbaiah Ramasamy Krishnadas, MD7, Christian Mardin, MD9, André Reis, PhD10, Jiyun Yang, MD1, Lin Zhang, PhD1,3, Yu Zhou, PhD1, Ziyan Wang, PhD1, Chao Qu, MD11, Peter X. Shaw, PhD12, Chi-Pui Pang, DPhil4, Xinghuai Sun, MD3, Weiquan Zhu, MD5, Dean Yaw Li, MD5, Francesca Pasutto, PhD10 and Zhenglin Yang, MD, PhD1,2 Purpose: Primary open-angle glaucoma (POAG) is the leading 4763 POAG patients, whereas no variants were detected in any cause of irreversible blindness worldwide and mutations in known exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s genes can only explain 5–6% of POAG. This study was conducted aggregated in transfected cells and resulted in damage to the AM- to identify novel POAG-causing genes and explore the pathogenesis RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 of this disease. allele led to cAMP reduction and retinal ganglion cell death in mice. Methods: Exome sequencing was performed in a Han Chinese Conclusion: This study demonstrated that disruption of RAMP2/ cohort comprising 398 sporadic cases with POAG and 2010 CRLR-cAMP axis could cause POAG and identified a potential controls, followed by replication studies by Sanger sequencing. A therapeutic intervention for POAG. heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. Genetics in Medicine (2019) 21:2345–2354; https://doi.org/10.1038/s41436- Results: Using exome sequencing analysis and replication studies, 019-0507-0 we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations Keywords: primary open-angle glaucoma (POAG); exome (Han Chinese, German, and Indian). Six heterozygous RAMP2 sequencing; receptor activity-modifying protein 2 (RAMP2); pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113- heterozygous pathogenic variant; retinal ganglion cell (RGC) Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of INTRODUCTION genetic and environmental factors play critical roles in the Glaucoma is a degenerative disease of the optic nerve that is development of POAG. From a genetic perspective, POAG can characterized by the death of retinal ganglion cells (RGCs), be caused by mutations in a single gene (monogenic form) or by with an increase in the vertical cup-to-disc ratio and losses in combined action of genetic and environmental factors (poly- the visual field.1 This condition is a leading cause of genic form). A mutation in MYOC (encoding myocilin),3 OPTN irreversible blindness worldwide; indeed, estimates suggest (encoding optineurin),4 WDR36 (encoding WD repeat domain that by 2020 there will be 79.6 million individuals affected 36),5 TBK1 (encoding TANK-binding kinase 1),6 and ASB10 with glaucoma.2 (encoding ankyrin repeat- and SOCS box-containing 10)7 could Primary open-angle glaucoma (POAG) is the most common result in POAG. The genetic risk factors for POAG have been type of glaucoma, and is diagnosed among a wide range of studied in the past decade using genome-wide association ethnic groups, including whites, blacks, and Asians.2 Both studies (GWAS), which have identified numerous associated Correspondence: Zhenglin Yang ([email protected]). #Affiliations are listed at the end of the paper. These authors contributed equally: Bo Gong, Houbin Zhang, Lulin Huang Submitted 7 August 2018; accepted: 20 March 2019 Published online: 19 April 2019 GENETICS in MEDICINE | Volume 21 | Number 10 | October 2019 2345 ARTICLE GONG et al genes/loci. These genes/loci include CAV1-CAV2,8,9 TMCO11,10 Sanger sequencing to identify other pathogenic variants – CDKN2B-AS1,10 SIX1-SIX6,11 ABCA1,9,12 14 PMM2,12 in the replication stage FNDC3B,13,15 AFAP1,14 GMDS,14 TGFBR3,16 TXNRD2,17 We first validated the two RAMP2 pathogenic variants in ATXN2,17 FOXC1,17 and the chromosomal regions include three POAG patients by Sanger sequencing and then 8q22 and 11p11.2.11,13 However, genetic variants associated sequenced more samples to identify other mutant RAMP2s. with these known genes/loci account for only 5–6% of all Sequencing primers for the coding sequences of RAMP2 patients with POAG,18,19 and the pathogenic mechanisms (NM_005854) were designed using Primer 5.0 (Supplemen- underpinning their role in the development of POAG remain tary Table 3). unclear. Although sporadic occurrences account for at least 28% Multiple sequence alignment of the human RAMP2 protein of all reported cases of POAG,20 the genes responsible for such was performed along with other RAMP2 proteins across cases are largely unknown due to several limitations: (1) different species to examine the conservation of the residues. traditional genetic studies for monogenic forms depend on large The possible damaging effects of the pathogenic variant on pedigrees, (2) genetic variants identified by GWAS using chip the structure and function of RAMP2 were predicted arrays generally are not in the coding regions of specific using SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, genes and represent genetic risk factors. Recent advances in Mutation Taster, Mutation Assessor, M-CAP, Fathmm- sequencing techniques and algorithms have made it possible to MKL, and CADD. identify pathogenic variants in the disease-related genes from sporadic cases. Expression constructs and mutagenesis The aims of the present study were to identify genes Human calcitonin receptor-like receptor (CRLR, NM_00579) associated with sporadic POAG and to determine how and RAMP2 complementary DNA (cDNA) ligated into the disruption of their normal biological functions might cause SgfI/MluI sites of a mammalian expression plasmid (pCMV6- 1234567890():,; this condition. We performed exome sequencing (ES) analysis myc/DDK) were obtained from OriGene. The RAMP2 using samples collected from 398 unrelated patients with plasmid was used as a template to generate specific mutations POAG and 2010 unrelated control individuals without of RAMP2 using the QuikChange II Site-Directed Mutagen- POAG, all of whom were Han Chinese ancestry. Then, the esis kit (Stratagene) (Supplementary Table 4). pathogenesis of POAG resulting from gene pathogenic variants identified in this study was further investigated. Cell culture and transfection COS-7 monkey kidney fibroblast-like cells and 293 T cells MATERIALS AND METHODS were maintained in 60-mm culture dishes (Corning) with Study participants Eagle’s Minimal Essential Medium (Invitrogen) supplemented This study included four cohorts of patients with POAG, with 10% fetal bovine serum (FBS; Invitrogen) and antibiotics characterized by high intraocular pressure (IOP), derived (1% penicillin–streptomycin; Invitrogen). Cells (105/cm2) from Han Chinese, German, and Indian populations were transfected with the wild-type (WT) or mutant RAMP2 (Supplementary Table 1). Written informed consent was constructs using Lipofectamine® 3000 Reagent (Invitrogen) in obtained from all subjects. This project was approved by the Opti-MEM® I (Invitrogen). Institutional Review Board of ophthalmic clinics at the following centers: Eye and Ear Nose Throat (ENT) Hospital, Expression analysis in human ocular tissues Fudan University; Hong Kong Eye Hospital at the Chinese A deceased 55-year-old Han Chinese male graciously donated University of Hong Kong; Sichuan Academy of Medical human ocular tissues. Total RNA from the optical nerve, Sciences and Sichuan Provincial People’s Hospital; Center for retina, iris, corneal, and trabecular meshwork was extracted Ophthalmology, University of Tuebingen; Department of with TRIzol (Invitrogen). Semiquantitative polymerase chain Ophthalmology at Universitätsklinikum Erlangen, Friedrich- reaction (PCR) was performed for RAMP2. A housekeeping Alexander-Universität Erlangen-Nürnberg; and India Aravind gene (GAPDH; NM_001256799.2) was used as an internal Hospital. All participants underwent an extensive ophthalmic control, with its transcripts amplified in parallel reactions. examination and were recruited according to standardized The sequences of the primers used for semiquantitative PCR criteria (see details in Supplementary Materials), and as are listed in Supplementary Table 5. described in a previous study.12 Immunofluorescence and western blotting Exome sequencing COS-7 cells (American Tissue Culture Collection, Manassas, We sequenced 2408 subjects at the first stage of the project, VA) and retinal sections were fixed, permeabilized, and including 398 POAG cases and 2010 controls, using Illumina followed by immunostaining (see details in Supplementary Truseq Enrichment System Capture (62 M) and following the Materials). Samples were imaged with a confocal microscope manufacturer’s instructions. The data filtering strategy was (Leica). Mouse retinas were lysed for transferring to a described in our previous study21 and a data production nitrocellulose membrane (Millipore) and followed by anti- summary of individuals in this study
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