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Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis.
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.
Affiliation
  • Gong B; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Zhang H; Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, Sichuan, China.
  • Huang L; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Chen Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Shi Y; Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat (ENT) Hospital, Fudan University, Shanghai, China.
  • Tam PO; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Zhu X; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • Huang Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Lei B; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Sundaresan P; Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA.
  • Li X; People's Hospital of Zhengzhou University and Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou, China.
  • Jiang L; Department of Genetics, Dr. G. Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, India Aravind Hospital, Tamilnadu, India.
  • Yang J; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Lin Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Lu F; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Chen L; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Li Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Leung CK; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • Guo X; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Zhang S; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • Huang G; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Wu Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Zhou T; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Shuai P; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Tham CC; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Weisschuh N; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Krishnadas SR; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • Mardin C; Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany.
  • Reis A; Department of Genetics, Dr. G. Venkataswamy Eye Research Institute, Aravind Medical Research Foundation, India Aravind Hospital, Tamilnadu, India.
  • Yang J; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Zhang L; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • Zhou Y; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Wang Z; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Qu C; Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat (ENT) Hospital, Fudan University, Shanghai, China.
  • Shaw PX; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Pang CP; The Key Laboratory for Human Disease Gene Study of Sichuan Province and Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Sun X; Department of Ophthalmology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • Zhu W; Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
  • Li DY; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • Pasutto F; Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat (ENT) Hospital, Fudan University, Shanghai, China.
  • Yang Z; Department of Medicine, Program in Molecular Medicine, University of Utah, Salt Lake City, UT, USA.
Genet Med ; 21(10): 2345-2354, 2019 10.
Article de En | MEDLINE | ID: mdl-31000793
ABSTRACT

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.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Glaucome à angle ouvert / Protéine-2 modifiant l'activité des récepteurs Type d'étude: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Animals / Humans / Male / Middle aged Pays/Région comme sujet: Asia Langue: En Journal: Genet Med Sujet du journal: GENETICA MEDICA Année: 2019 Type de document: Article Pays d'affiliation: Chine
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Glaucome à angle ouvert / Protéine-2 modifiant l'activité des récepteurs Type d'étude: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limites: Animals / Humans / Male / Middle aged Pays/Région comme sujet: Asia Langue: En Journal: Genet Med Sujet du journal: GENETICA MEDICA Année: 2019 Type de document: Article Pays d'affiliation: Chine