RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype–phenotype association
Corresponding Author
Kaoru Fujinami
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
Correspondence
Kaoru Fujinami, Laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, No. 2-5-1, Higashigaoka, Meguro-ku, Tokyo 152-8902 Japan.
Email: [email protected]
Search for more papers by this authorXiao Liu
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorShinji Ueno
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAtsushi Mizota
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Search for more papers by this authorKei Shinoda
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Department of Ophthalmology, Saitama Medical University, Moroyama Campus, Saitama, Japan
Search for more papers by this authorKazuki Kuniyoshi
Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
Search for more papers by this authorYu Fujinami-Yokokawa
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan
Division of Public Health, Yokokawa Clinic, Suita, Japan
Search for more papers by this authorLizhu Yang
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorGavin Arno
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
North East Thames Regional Genetics Service, UCL Great Ormond Street Institute of Child Health, NHS Foundation Trust, London, UK
Search for more papers by this authorNikolas Pontikos
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
Search for more papers by this authorShuhei Kameya
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
Search for more papers by this authorTaro Kominami
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHiroko Terasaki
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHiroyuki Sakuramoto
Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
Search for more papers by this authorNatsuko Nakamura
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorToshihide Kurihara
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorKazuo Tsubota
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorYozo Miyake
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Aichi Medical University, Nagakute, Japan
Next vision, Kobe Eye Center, Kobe, Japan
Search for more papers by this authorKazutoshi Yoshiake
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorTakeshi Iwata
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorKazushige Tsunoda
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorJapan Eye Genetics Consortium Study Group
Search for more papers by this authorCorresponding Author
Kaoru Fujinami
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
Correspondence
Kaoru Fujinami, Laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, No. 2-5-1, Higashigaoka, Meguro-ku, Tokyo 152-8902 Japan.
Email: [email protected]
Search for more papers by this authorXiao Liu
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China
Search for more papers by this authorShinji Ueno
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAtsushi Mizota
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Search for more papers by this authorKei Shinoda
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Department of Ophthalmology, Saitama Medical University, Moroyama Campus, Saitama, Japan
Search for more papers by this authorKazuki Kuniyoshi
Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
Search for more papers by this authorYu Fujinami-Yokokawa
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan
Division of Public Health, Yokokawa Clinic, Suita, Japan
Search for more papers by this authorLizhu Yang
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorGavin Arno
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
North East Thames Regional Genetics Service, UCL Great Ormond Street Institute of Child Health, NHS Foundation Trust, London, UK
Search for more papers by this authorNikolas Pontikos
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
UCL Institute of Ophthalmology, London, UK
Moorfields Eye Hospital, London, UK
Search for more papers by this authorShuhei Kameya
Department of Ophthalmology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
Search for more papers by this authorTaro Kominami
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHiroko Terasaki
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHiroyuki Sakuramoto
Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
Search for more papers by this authorNatsuko Nakamura
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Department of Ophthalmology, Teikyo University, Tokyo, Japan
Department of Ophthalmology, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorToshihide Kurihara
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorKazuo Tsubota
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorYozo Miyake
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Aichi Medical University, Nagakute, Japan
Next vision, Kobe Eye Center, Kobe, Japan
Search for more papers by this authorKazutoshi Yoshiake
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorTakeshi Iwata
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorKazushige Tsunoda
Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
Search for more papers by this authorJapan Eye Genetics Consortium Study Group
Search for more papers by this authorKaoru Fujinami and Xiao Liu are joint first authors of this study.
Funding information: FOUNDATION FIGHTING BLINDNESS ALAN LATIES CAREER DEVELOPMENT PROGRAM, Grant/Award Number: CF-CL-0416-0696-UCL; Grant-in-Aid for Scientists to support international collaborative studies of the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grant/Award Number: 16KK01930002; Grant-in-Aid for Young Scientists (A) of the Ministry of Education, Culture, Sports, Science and Technology, Japan, Grant/Award Number: 16H06269; Great Britain Sasakawa Foundation Butterfield Awards; Health Labour Sciences Research Grant, The Ministry of Health Labour and Welfare, Grant/Award Number: 201711107A; National Hospital Organization Network Research Fund, Grant/Award Number: H30-NHO-Sensory Organs-03; Novartis Research Grant; Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science, Japan, Grant/Award Number: H26-26462674; Ministry of Health, Labor and Welfare, Grant/Award Number: 18ek0109282h0002; Japan Agency for Medical Research and Development (AMED); ROHTO Pharmaceutical Co., Ltd.; Santen Pharmaceutical Co. Ltd.; Novartis Pharmaceuticals; Kowa Company, Ltd.; Kirin Company, Ltd.; Fuji Xerox Co., Ltd.; Tsubota Laboratory, Inc.; UCL Institute of Ophthalmology; Great Britain Sasakawa Foundation Butterfield Award; UCL Institute of Child Health; Great Ormond Street Hospital; Moorfields Eye Hospital; Ministry of Education, Culture, Sports, Science and Technology, Grant/Award Number: 18K16943
Abstract
The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10–47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52–2.0)/1.10 (0.52–1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.
CONFLICT OF INTEREST
All authors have completed and submitted the ICMJE Form for disclosure of potential conflicts of interest. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor but may receive a salary or other support from the institution to support their effort on the project(s).
Kaoru Fujinami is a paid Consultant for Astellas Pharma Inc., Kubota Pharmaceutical Holdings Co., Ltd., Acucela Inc., Novartis AG, Janssen Pharmaceutica, Sanofi Genzyme, NightstaRx Limited; reports personal fees from Astellas Pharma Inc., Kubota Pharmaceutical Holdings Co., Ltd., Acucela Inc., Novartis AG, Santen Company Limited, Foundation Fighting Blindness, Foundation Fighting Blindness Clinical Research Institute, Japanese Ophthalmology Society, Japan Retinitis Pigmentosa Society; reports grants from Astellas Pharma Inc. (NCT03281005), outside the submitted work.
Toshihide Kurihara is an investor in Tsubota Laboratory, Inc. and RestoreVision, Inc. Toshihide Kurihara reports grants and personal fees from ROHTO Pharmaceutical Co., Ltd., Tsubota Laboratory, Inc., Fuji Xerox Co., Ltd., Kowa Company, Ltd., Santen Pharmaceutical Co. Ltd., outside the submitted work.
Kazuo Tsubota reports grants and personal fees from Santen Pharmaceutical Co., Ltd., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Wakamoto Pharmaceutical Co., Ltd., grants from ROHTO Pharmaceutical Co., Ltd., grants from R-Tech Ueno, personal fees from Laboratoires Thea, grants from Alcon Japan, investor of Tear Solutions, grants and investor of Tsubota Laboratory, Inc., outside the submitted work.
Supporting Information
| Filename | Description |
|---|---|
| ajmgc31830-sup-0001-supinfo.zipapplication/x-zip-compressed, 1.4 MB | Figure S1 Molecular modeling of missense variants Molecular modeling of four missense variants was performed with YASARA software (http://www.yasara.org/) based on a Swiss model (O75695; XRP2_HUMAN; https://swissmodel.expasy.org/): c.566T>C (p.Leu189Pro) detected in the current study and c.353G>A (p.Arg118His); c.413A>G (p.Glu138Gly); and c.758T>G (p.Leu253Arg) from previous reports. Modeling for one variant (c.17C>T [p.Ser6Phe]) was not available. Table S1. Primers for the direct screening of the detected RP2 variants Table S2. Summary of detected variants of four affected and four unaffected individuals from four families with RP2-associated retinal disorder Table S3. Depth and coverage of four detected RP2 variants Table S4. Genotype–phenotype association of RP2-RD in the Japanese population Data S1. Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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