Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The central retinal thickness and its related genotype in ABCA4-related retinopathy

Eye (2024)Cite this article

Subjects

Abstract

Purpose

To further explore the influence of genotype, including mutation type and structural domain, on the severity of macular atrophy, we measured the central retinal thickness (CRT) in patients with ABCA4-related retinopathy.

Methods

A total of 66 patients were included in the cohort. This was a retrospective investigation. The patients were tested using whole exon sequencing and ophthalmic exams, including slip lamp exams, best-corrected visual acuity, optical coherence tomography, fundus photo, and fundus autofluorescence.

Results

In this study, we discovered that mutations on nucleotide binding domains (NBD) lead to less CRT (45.00 ± 25.25μm, 95% CI: 31.54–58.46) had significantly less CRT than the others (89.75 ± 71.17μm, 95% CI: 30.25–149.25, p = 0.032), and could accelerate the rate of CRT decrease.

Conclusions

Our study provides new perspectives in the understanding of ABCA4-related retinopathy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Distribution of mutations on ABCA4.
Fig. 2: Representative images of P11 and P25.

Similar content being viewed by others

Data availability

The datasets generated and/or analysed during the current study are not publicly available due funding requirement but are available from the corresponding author on reasonable request.

References

  1. Tracewska AM, Kocyła-Karczmarewicz B, Rafalska A, Murawska J, Jakubaszko-Jablonska J, Rydzanicz M, et al. Genetic Spectrum of ABCA4-Associated Retinal Degeneration in Poland. Genes. 2019;10:959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Birtel J, Eisenberger T, Gliem M, Müller PL, Herrmann P, Betz C, et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018;8:4824.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Adv Exp Med Biol. 2010;703:105–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Molday RS, Garces FA, Scortecci JF, Molday LL. Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration. Prog Retin Eye Res. 2021;89:101036.

    Article  PubMed  Google Scholar 

  5. Huang WC, Cideciyan AV, Roman AJ, Sumaroka A, Sheplock R, Schwartz SB, et al. Inner and outer retinal changes in retinal degenerations associated with ABCA4 mutations. Invest Ophthalmol Vis Sci. 2014;55:1810–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen Y, Okano K, Maeda T, Chauhan V, Golczak M, Maeda A, et al. Mechanism of all-trans-retinal toxicity with implications for Stargardt disease and age-related macular degeneration. J Biol Chem. 2012;287:5059–69.

    Article  CAS  PubMed  Google Scholar 

  7. Fujinami K, Lois N, Mukherjee R, McBain VA, Tsunoda K, Tsubota K, et al. A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations. Invest Ophthalmol Vis Sci. 2013;54:8181–90.

    Article  PubMed  Google Scholar 

  8. Mucciolo DP, Lippera M, Giorgio D, Sodi A, Passerini I, Cipollini F, et al. Outer nuclear layer relevance in visual function correlated to quantitative enface OCT parameters in Stargardt disease. Eur J Ophthalmol. 2021;31:3248–58.

    Article  PubMed  Google Scholar 

  9. Whitmore SS, Fortenbach CR, Cheng JL, DeLuca AP, Critser DB, Geary EL, et al. Analysis of retinal sublayer thicknesses and rates of change in ABCA4-associated Stargardt disease. Sci Rep. 2020;10:16576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Holtan JP, Aukrust I, Jansson RW, Berland S, Bruland O, Gjerde BL, et al. Clinical features and molecular genetics of patients with ABCA4-retinal dystrophies. Acta Ophthalmol. 2021;99:e733–46.

    Article  CAS  PubMed  Google Scholar 

  11. Heath Jeffery RC, Thompson JA, Lo J, Lamey TM, McLaren TL, McAllister IL, et al. Genotype-specific lesion growth rates in Stargardt disease. Genes. 2021;12:1981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Joo K, Seong MW, Park KH, Park SS, Woo SJ. Genotypic profile and phenotype correlations of ABCA4-associated retinopathy in Koreans. Mol Vis. 2019;25:679–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu Q, Rui X, Li Y, You Y, Sheng XL, Lei B. Identification of four novel variants and determination of genotype-phenotype correlations for ABCA4 variants associated with inherited retinal degenerations. Front Cell Dev Biol. 2021;9:634843.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chen Z, Chen J, Gao M, Liu Y, Wu Y, Wang Y, et al. Comprehensive analysis of the PRPF31 gene in retinitis pigmentosa patients: Four novel Alu-mediated copy number variations at the PRPF31 locus. Hum Mutat. 2022;43:2279–94.

    Article  CAS  PubMed  Google Scholar 

  15. Jin P, Zou H, Zhu J, Xu X, Jin J, Chang TC, et al. Choroidal and retinal thickness in children with different refractive status measured by swept-source optical coherence tomography. Am J Ophthalmol. 2016;168:164–76.

    Article  PubMed  Google Scholar 

  16. Ciulla TA, Kapik B, Grewal DS, Ip MS. Visual acuity in retinal vein occlusion, diabetic, and uveitic macular edema: central subfield thickness and ellipsoid zone analysis. Ophthalmol Retin. 2021;5:633–47.

    Article  Google Scholar 

  17. Wang Y, Chen J, Zhang M, Yu S, Gong Y, Lin F, et al. Genetic factors and characteristics on spectral-domain optical coherence tomography are associated to choroidal thickness in ABCA4-related retinopathy factors of choroidal thickness in ABCA4 retinopathy. Retina. 2024;44:166–74.

  18. Khan KN, Kasilian M, Mahroo OAR, Tanna P, Kalitzeos A, Robson AG, et al. Early patterns of macular degeneration in ABCA4-associated retinopathy. Ophthalmology. 2018;125:735–46.

    Article  PubMed  Google Scholar 

  19. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017;101:25–30.

    Article  PubMed  Google Scholar 

  20. van Huet RA, Bax NM, Westeneng-Van Haaften SC, Muhamad M, Zonneveld-Vrieling MN, Hoefsloot LH, et al. Foveal sparing in Stargardt disease. Invest Ophthalmol Vis Sci. 2014;55:7467–78.

    Article  PubMed  Google Scholar 

  21. Westeneng-van Haaften SC, Boon CJ, Cremers FP, Hoefsloot LH, den Hollander AI, Hoyng CB. Clinical and genetic characteristics of late-onset Stargardt’s disease. Ophthalmology. 2012;119:1199–210.

    Article  PubMed  Google Scholar 

  22. Fujinami K, Sergouniotis PI, Davidson AE, Wright G, Chana RK, Tsunoda K, et al. Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function. Am J Ophthalmol. 2013;156:487–501.e1.

    Article  CAS  PubMed  Google Scholar 

  23. Burke TR, Fishman GA, Zernant J, Schubert C, Tsang SH, Smith RT, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2012;53:4458–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Aksentijevich I, Schnappauf O. Molecular mechanisms of phenotypic variability in monogenic autoinflammatory diseases. Nat Rev Rheumatol. 2021;17:405–25.

    Article  CAS  PubMed  Google Scholar 

  25. Rees DC, Johnson E, Lewinson O. ABC transporters: the power to change. Nat Rev Mol Cell Biol. 2009;10:218–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu F, Lee J, Chen J. Molecular structures of the eukaryotic retinal importer ABCA4. Elife. 2021;10:218–27.

    Google Scholar 

  27. Scortecci JF, Molday LL, Curtis SB, Garces FA, Panwar P, Van Petegem F, et al. Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease. Nat Commun. 2021;12:5902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Xie T, Zhang Z, Fang Q, Du B, Gong X. Structural basis of substrate recognition and translocation by human ABCA4. Nat Commun. 2021;12:3853.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hu FY, Gao FJ, Li JK, Xu P, Wang DD, Zhang SH, et al. Novel variants of ABCA4 in Han Chinese families with Stargardt disease. BMC Med Genet. 2020;21:213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rosenberg T, Klie F, Garred P, Schwartz M. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007;13:1962–9.

    CAS  PubMed  Google Scholar 

  31. Ahn J, Beharry S, Molday LL, Molday RS. Functional interaction between the two halves of the photoreceptor-specific ATP binding cassette protein ABCR (ABCA4). Evidence for a non-exchangeable ADP in the first nucleotide binding domain. J Biol Chem. 2003;278:39600–8.

    Article  CAS  PubMed  Google Scholar 

  32. Al-Khuzaei S, Broadgate S, Foster CR, Shah M, Yu J, Downes SM, et al. An overview of the genetics of ABCA4 retinopathies, an evolving story. Genes. 2021;12:1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee W, Nõupuu K, Oll M, Duncker T, Burke T, Zernant J, et al. The external limiting membrane in early-onset Stargardt disease. Invest Ophthalmol Vis Sci. 2014;55:6139–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by National Natural Science Foundation of China (82171076 and 82101159), Science and Technology Commission of Shanghai Municipality (20Z11900400), Shanghai Hospital Development Center (SHDC2020CR2040B, SHDC2020CR5014), Shanghai Collaborative Innovation Center for Translational Medicine (TM202115PT) and Shanghai Sailing Program (22YF1435500).

Author information

Author notes

  1. These authors contributed equally: Yimin Wang, Tong Li.

Authors and Affiliations

  1. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yimin Wang, Tong Li, Suqin Yu, Yuanyuan Gong, Min Zhang, Yidong Wu, Wenjia Liu, Junran Sun, Jieqiong Chen & Xiaodong Sun

  2. Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, China

    Yimin Wang, Fei Yuan & Yimin Wang

  3. National Clinical Research Center for Eye Disease, Shanghai, China

    Tong Li, Suqin Yu, Yuanyuan Gong, Min Zhang, Yidong Wu, Wenjia Liu, Junran Sun, Jieqiong Chen & Xiaodong Sun

  4. Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China

    Tong Li, Suqin Yu, Yuanyuan Gong, Min Zhang, Yidong Wu, Wenjia Liu, Junran Sun, Jieqiong Chen & Xiaodong Sun

  5. Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China

    Tong Li, Suqin Yu, Yuanyuan Gong, Min Zhang, Yidong Wu, Wenjia Liu, Junran Sun, Jieqiong Chen & Xiaodong Sun

  6. National Clinical Research Center for Ophthalmic Diseases, Shanghai, China

    Xiaodong Sun, Suqin Yu, Yuanyuan Gong, Jieqiong Chen, Wenjia Liu, Xiaoling Wan, Tong Li, Yang Yu & Huixun Jia

  7. Department of Ophthalmology, Shanghai General Hospital, Shanghai, China

    Xiaodong Sun, Suqin Yu, Yuanyuan Gong, Jieqiong Chen, Wenjia Liu, Xiaoling Wan, Tong Li, Yang Yu & Huixun Jia

  8. Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xi Shen

  9. Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China

    Zhiliang Wang

  10. Department of Ophthalmology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    Tong Qiao

  11. Department of Ophthalmology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China

    Qiang Wu

  12. Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yu Xu

  13. Department of Ophthalmology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Chaoyang Wang

  14. Department of Ophthalmology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China

    Chenhao Yang

  15. Department of Ophthalmology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University, Shanghai, China

    Jifang Qu

  16. Department of Medical Genetics, School of Medicine, Tongji University, Shanghai, 200092, China

    Jianjun Chen

Authors
  1. Yimin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suqin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuanyuan Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yidong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenjia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Junran Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jieqiong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaodong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Shanghai Inherited Retinal Disease (SHIRD) Study Group

  • Xiaodong Sun
  • , Suqin Yu
  • , Yuanyuan Gong
  • , Jieqiong Chen
  • , Wenjia Liu
  • , Xiaoling Wan
  • , Tong Li
  • , Yang Yu
  • , Huixun Jia
  • , Fei Yuan
  • , Yimin Wang
  • , Xi Shen
  • , Zhiliang Wang
  • , Tong Qiao
  • , Qiang Wu
  • , Yu Xu
  • , Chaoyang Wang
  • , Chenhao Yang
  • , Jifang Qu
  •  & Jianjun Chen

Contributions

All authors read and approved the final manuscript. (1) Conceived and designed the experiments(JQC); (2) the acquisition of data (YMW, TL, SQY, YYG, YDW, JRS, XDS); (3) Analysed and interpreted the data (YMW, TL,WJL); (4) Contributed analysis tools or data (YMW, TL, JQC, XDS); (5) drafting the article or critically revising its important intellectual content (YMW, TL, JQC, XDS); (6) final approval of the version submitted (YMW, TL, SQY, YYG, JQC, XDS).

Corresponding author

Correspondence to Jieqiong Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participants

This study was approved by the ethical committee of Shanghai General Hospital and conformed to the Declaration of Helsinki. Written informed consent was obtained from the patients or parents of our patient.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Li, T., Yu, S. et al. The central retinal thickness and its related genotype in ABCA4-related retinopathy. Eye (2024). https://doi.org/10.1038/s41433-024-03104-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41433-024-03104-2

Search

Advanced search

Quick links