To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan
Retrospective multicenter study
In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions.
The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region.
We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.
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Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795–809.
Campochiaro PA, Mir TA. The mechanism of cone cell death in retinitis pigmentosa. Prog Retin Eye Res. 2018;62:24–37.
Morizane Y, Morimoto N, Fujiwara A, Kawasaki R, Yamashita H, Ogura Y, et al. Incidence and causes of visual impairment in Japan: the first nation-wide complete enumeration survey of newly certified visually impaired individuals. Jpn J Ophthalmol. 2019;63:26–33.
Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, Klaver CCW, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157–86.
Dias MF, Joo K, Kemp JA, Fialho SL, da Silva CA, Woo SJ, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res. 2018;63:107–31.
Nishiguchi KM, Fujita K, Miya F, Katayama S, Nakazawa T. Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice. Nat Commun. 2020;11:482.
Carrigan M, Duignan E, Malone CP, Stephenson K, Saad T, McDermott C, et al. Panel-based population next-generation sequencing for inherited retinal degenerations. Sci Rep. 2016;6:33248.
Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100:75–90.
Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124:1314–31.
Ellingford JM, Barton S, Bhaskar S, O’Sullivan J, Williams SG, Lamb JA, et al. Molecular findings from 537 individuals with inherited retinal disease. J Med Genet. 2016;53:761–7.
Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and Usher syndrome patients by next-generation sequencing. Investig Ophthalmol Vis Sci. 2014;55:7369–75.
Gao F-J, Li J-K, Chen H, Hu F-Y, Zhang S-H, Qi Y-H, et al. Genetic and clinical findings in a large cohort of Chinese patients with suspected retinitis pigmentosa. Ophthalmology. 2019;126:1549–56.
Maeda A, Yoshida A, Kawai K, Arai Y, Akiba R, Inaba A, et al. Development of a molecular diagnostic test for retinitis pigmentosa in the Japanese population. Jpn J Ophthalmol. 2018;62:451–7.
Pontikos N, Arno G, Jurkute N, Schiff E, Ba-Abbad R, Malka S, et al. Genetic basis of inherited retinal disease in a molecularly characterized cohort of more than 3000 families from the United Kingdom. Ophthalmology. 2020;127:1384–94.
Koyanagi Y, Akiyama M, Nishiguchi KM, Momozawa Y, Kamatani Y, Takata S, et al. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients. J Med Genet. 2019;56:662–70.
Hayakawa M, Matsumura M, Ohba N, Matsui M, Fujiki K, Kanai A, et al. A multicenter study of typical retinitis pigmentosa in Japan. Jpn J Ophthalmol. 1993;37:156–64.
Hayakawa M, Fujiki K, Kanai A, Matsumura M, Honda Y, Sakaue H, et al. Multicenter genetic study of retinitis pigmentosa in Japan: I. Genetic heterogeneity in typical retinitis pigmentosa. Jpn J Ophthalmol. 1997;41:1–6.
Hayakawa M, Fujiki K, Kanai A, Matsumura M, Honda Y, Sakaue H, et al. Multicenter genetic study of retinitis pigmentosa in Japan: II. Prevalence of autosomal recessive retinitis pigmentosa. Jpn J Ophthalmol. 1997;41:7–11.
Ikesugi K, Ichio T, Tsukitome H, Kondo M. Annual incidences of visual impairment during 10-year period in Mie prefecture. Japan Jpn J Ophthalmol. 2017;61:293–8.
Momozawa Y, Akiyama M, Kamatani Y, Arakawa S, Yasuda M, Yoshida S, et al. Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population. Hum Mol Genet. 2016;25:5027–34.
Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133:1–9.
Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–5.
Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Exome Aggregation C. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Dryja TP, McGee TL, Hahn LB, Cowley GS, Olsson JE, Reichel E, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med. 1990;323:1302–7.
Nakazawa M, Kikawa-Araki E, Shiono T, Tamai M. Analysis of rhodopsin gene in patients with retinitis pigmentosa using allele-specific polymerase chain reaction. Jpn J Ophthalmol. 1991;35:386–93.
Shiono T, Hotta Y, Noro M, Sakuma T, Tamai M, Hayakawa M, et al. Clinical features of Japanese family with autosomal dominant retinitis pigmentosa caused by point mutation in codon 347 of rhodopsin gene. Jpn J Ophthalmol. 1992;36:69–75.
Hosono K, Ishigami C, Takahashi M, Park DH, Hirami Y, Nakanishi H, et al. Two novel mutations in the EYS gene are possible major causes of autosomal recessive retinitis pigmentosa in the Japanese population. PLoS ONE. 2012;7:e31036.
Iwanami M, Oshikawa M, Nishida T, Nakadomari S, Kato S. High prevalence of mutations in the EYS gene in Japanese patients with autosomal recessive retinitis pigmentosa. Investig Ophthalmol Vis Sci. 2012;53:1033–40.
We acknowledge the staff of the Laboratory for Statistical Analysis and Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences. We would like to show our appreciation to J. Funatsu, T. Tachibana, K. Fujiwara, and S. Nakatake for collecting the samples and clinical data at Kyushu University Hospital. The patients were recruited through the Japan Retinitis Pigmentosa Registry Project (https://convention.jtbcom.co.jp/jrprp/).
This work was supported by Japan Agency for Medical Research and Development grants 17ek0109213h0002 (to K.M.N.) and by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant 17K111447, to Y.H.).
These funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
Y. Koyanagi, None; M. Akiyama, Endowed (NIDEK), Lecture fee (Novartis, Takeda, Mitsubishi Tanabe); K. M. Nishiguchi, None; Y. Momozawa, None; Y. Kamatani, None; S. Takata, None; C. Inai, None; Y. Iwasaki, None; M. Kumano, None; Y. Murakami, Grant (Charitable Trust Fund for Ophthalmic Research in Commemoration of Santen Pharmaceutical's Founder, Bayer, Takeda Science Foundation), Lecture fee (Novartis, Bayer, Santen, AMO, Senju, Astellas); S. Komori, None; D. Gao, None; K. Kurata, None; K. Hosono, None; S. Ueno, Lecture fee (Novartis, TOMEY, NIDEK, HOYA, Santen, Nikon); Y. Hotta, None; A. Murakami, Grant, Financial support (Johnson & Johnson, Alcon, Otsuka, Kowa), Financial support (LION), Grant (IWAKI OPTICAL, Santen, AMO, Eisai, SEED, Senju, Novartis, Pfizer, HOYA, ROHTO); H. Terasaki, Grant, Honoraria for lecturing (Alcon, Bayer, Eizai, Novartis, Santen, Senju, Wakamoto, Otsuka, Kowa), Honoraria for lecturing, Non-financial support (ZEISS), Grant (AMO, HOYA), Honoraria for lecturing (Sanofi, AbbVie), Honoraria (ROHTO); Y. Wada, None; T. Nakazawa, Grant, Consultant fee, Lecture fee, Speaker fee (Santen, Senju), Grant, Lecture fee, Speaker fee (Topcon), Grant (NIDEK); T. Ishibashi, None; Y. Ikeda, Grant, Lecture fee, Consultant fee (HOYA), Grant (NIDEK); M. Kubo, None; K. Sonoda, None.
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Corresponding Author: Masato Akiyama
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Koyanagi, Y., Akiyama, M., Nishiguchi, K.M. et al. Regional differences in genes and variants causing retinitis pigmentosa in Japan. Jpn J Ophthalmol 65, 338–343 (2021). https://doi.org/10.1007/s10384-021-00824-w
- Next-generation sequencing
- Retinitis pigmentosa