Skip to main content
SpringerLink
Log in

A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa

  • Laboratory Investigation
  • Published:
Japanese Journal of Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To screen for the 328 bp Alu insertion (c.4052_4053ins328, p.Tyr1352Alafs) in RP1 in a group of retinitis pigmentosa (RP) patients who had been previously identified with a heterozygous deleterious mutation in the gene.

Study design

Prospective, clinical and experimental study.

Methods

The Alu insertion in RP1 was screened with an optimized PCR-based method in 26 RP patients with a heterozygous deleterious mutation (nonsense or frameshift) in RP1 that had been identified in a preceding genetic study. The genetic location of the previously identified mutation and its inheritance pattern were assessed.

Results

Out of 26 RP patients with a heterozygous deleterious mutation in RP1, 5 (19.2%) were found to carry an additional heterozygous Alu insertion, presumably resulting in a compound heterozygous state. This included 3 patients who had been previously diagnosed as autosomal dominant RP based on genetic findings. They were re-diagnosed as having an autosomal recessive disease following our new findings. In all patients identified with the Alu insertion, the other mutations found in the preceding study were outside the defined region in exon 4 (encoding amino acids 677 to 917) in which truncation mutations have been suggested to exert a dominant negative effect.

Conclusion

The founder Alu insertion in RP1 is an important cause of autosomal recessive RP in Japanese patients and can be missed in standard targeted resequencing. Screening optimized for this mutation is warranted, particularly in patients with a heterozygous deleterious mutation outside the defined region in exon 4 of RP1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Liu Q, Zhou J, Daiger SP, Farber DB, Heckenlively JR, Smith JE, et al. Identification and subcellular localization of the RP1 protein in human and mouse photoreceptors. Investig Ophthalmol Vis Sci. 2002;43:22–32.

    Google Scholar 

  2. Liu Q, Zuo J, Pierce EA. The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein. J Neurosci. 2004;24:6427–36.

    Article  CAS  Google Scholar 

  3. Pierce EA, Quinn T, Meehan T, McGee TL, Berson EL, Dryja TP. Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet. 1999;22:248.

    Article  CAS  Google Scholar 

  4. Guillonneau X, Piriev NI, Danciger M, Kozak CA, Cideciyan AV, Jacobson SG, et al. A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus. Hum Mol Genet. 1999;8:1541–6.

    Article  CAS  Google Scholar 

  5. Sullivan LS, Heckenlively JR, Bowne SJ, Zuo J, Hide WA, Gal A, et al. Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Nat Genet. 1999;22:255.

    Article  CAS  Google Scholar 

  6. Khaliq S, Abid A, Ismail M, Hameed A, Mohyuddin A, Lall P, et al. Novel association of RP1 gene mutations with autosomal recessive retinitis pigmentosa. J Med Genet. 2005;42:436–8.

    Article  CAS  Google Scholar 

  7. Avila-Fernandez A, Corton M, Nishiguchi KM, Muñoz-Sanz N, Benavides-Mori B, Blanco-Kelly F, et al. Identification of an RP1 prevalent founder mutation and related phenotype in Spanish patients with early-onset autosomal recessive retinitis. Ophthalmology. 2012;119:2616–21.

    Article  Google Scholar 

  8. Corton M, Nishiguchi KM, Avila-Fernández A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, et al. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One. 2013;8:e65574.

    Article  CAS  Google Scholar 

  9. Verbakel SK, van Huet RA, den Hollander AI, Geerlings MJ, Kersten E, Klevering BJ, et al. Macular dystrophy and cone-rod dystrophy caused by mutations in the RP1 gene: extending the RP1 disease spectrum. Investig Ophthalmol Vis Sci. 2019;60:1192–203.

    Article  CAS  Google Scholar 

  10. Riera M, Abad-Morales V, Navarro R, Ruiz-Nogales S, Méndez-Vendrell P, Corcostegui B, et al. Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy. Br J Ophthalmol. 2020;104:173–81.

    Article  Google Scholar 

  11. Lykke-Andersen S, Jensen TH. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol. 2015;16:665.

    Article  CAS  Google Scholar 

  12. 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. https://doi.org/10.1136/jmedgenet-2018-105691.

    Article  PubMed  Google Scholar 

  13. Nanda A, McClements ME, Clouston P, Shanks ME, MacLaren RE. The location of exon 4 mutations in RP1 raises challenges for genetic counseling and gene therapy. Am J Ophthalmol. 2019;202:23–9.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. Nishiguchi KM, Ikeda Y, Fujita K, Kunikata H, Akiho M, Hashimoto K, et al. Phenotypic features of Oguchi disease and retinitis pigmentosa in patients with S-antigen (SAG) mutations. Ophthalmology. 2019;126:1557–66.

    Article  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Taira K, Nakazawa M, Sato M. Mutation c. 1142 del G in the PRPF31 gene in a family with autosomal dominant retinitis pigmentosa (RP11) and its implications. Jpn J Ophthalmol. 2007;51:45–8.

    Article  CAS  Google Scholar 

  19. Katagiri S, Akahori M, Sergeev Y, Yoshitake K, Ikeo K, Furuno M, et al. Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa. PLoS One. 2014;9:e108721.

    Article  Google Scholar 

  20. Nikopoulos K, Cisarova K, Quinodoz M, Koskiniemi-Kuendig H, Miyake N, Farinelli P, et al. A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Nat Commun. 2019;10:2884.

    Article  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Kawamura M, Wada Y, Noda Y, Itabashi T, Ogawa S-I, Sato H, et al. Novel 2336-2337delCT mutation in RP1 gene in a Japanese family with autosomal dominant retinitis pigmentosa. Am J Ophthalmol. 2004;137:1137–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported in part by the Japan Agency for Medical Research and Development (#19ek0109213h0001, Nishiguchi). The manuscript was edited by a professional English editing service (Mr. Tim Hilts). The patients were recruited through the Japanese Retinitis Pigmentosa Registry Project (JRPRP).

Author information

Authors and Affiliations

  1. Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi-ken, 980-8574, Japan

    Koji Miura Nishiguchi & Toru Nakazawa

  2. Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Koji Miura Nishiguchi, Hiroshi Kunikata & Toru Nakazawa

  3. Department of Ophthalmic Imaging and Information Analytics, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Kosuke Fujita & Toru Nakazawa

  4. Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yasuhiro Ikeda, Yoshito Koyanagi, Masato Akiyama & Koh-Hei Sonoda

  5. Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Hiroshi Kunikata & Toru Nakazawa

  6. Division of Clinical Cell Therapy, Center for Translational and Advanced Animal Research, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan

    Toshiaki Abe

  7. Yuko Wada Eye Clinic, Sendai, 980-0011, Japan

    Yuko Wada

Authors
  1. Koji Miura Nishiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kosuke Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuhiro Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroshi Kunikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshito Koyanagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masato Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshiaki Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuko Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Koh-Hei Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toru Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Miura Nishiguchi.

Ethics declarations

Conflicts of interest

K. M. Nishiguchi, None; K. Fujita, Grant (NIDEK, TOPCON); Y. Ikeda, Grant (HOYA, Bayer, Santen), Lecture fee (HOYA, Nidek, Bayer, Santen, Alcon), Consultant fee (HOYA, Santen); H. Kunikata, None; Y. Koyanagi, None; M. Akiyama, None; T. Abe, None; Y. Wada, None; K. Sonoda, None; T. Nakazawa, None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Corresponding Author: Koji M Nishiguchi

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nishiguchi, K.M., Fujita, K., Ikeda, Y. et al. A founder Alu insertion in RP1 gene in Japanese patients with retinitis pigmentosa. Jpn J Ophthalmol 64, 346–350 (2020). https://doi.org/10.1007/s10384-020-00732-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10384-020-00732-5

Keywords

Search

Navigation