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:

Phenotypic characterization of autosomal dominant progressive cone dystrophies associated with a heterozygous variant c.2512C>T of GUCY2D gene in a large kindred

Eye volume 37, pages 2461–2469 (2023)Cite this article

Subjects

Abstract

Purpose

In this study, we described a large family presenting different manifestations of cone dystrophy at different ages associated with GUCY2D gene mutation.

Method

Sixty-three individuals of a single kindred, including 23 affected with cone dystrophies, were recruited and received ocular examinations, including best corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, color fundus photograph (CFP), fundus autofluorescence, optical coherence tomography, fluorescence fundus angiography, color vision testing, full-field electroretinography, and electro-oculogram. Whole exome sequencing (WES) and Sanger sequencing were performed for underlying mutations associated with cone dystrophy.

Result

There were 23 affected family members. Clinical analysis showed that the proband and other patients had impaired visual acuity ranging from 20/800 to 20/50 with impaired color vision. Fundus photograph showed retinal pigment epithelium (RPE) granular abnormalities with depressed macular reflex in young patients and macular or retinochoriodal atrophy in older patients. OCT examination confirmed the reduced outer retinal thickness or inner retinal thickness, absence of the ellipsoid zone (EZ) and retinal atrophy to varying degrees. Electroretinography revealed a reduced cone response combined with a relatively maintained rod response. WES and Sanger sequencing revealed a heterozygous variant c.2512C>T in the GUCY2D gene of the affected family members.

Conclusions

We reported cone dystrophy in 23 affected individuals in a five-generation family and demonstrated different macular abnormalities in OCT scans and CFP at different ages. The multimodal ocular records in our study provide physicians and ophthalmologists with a better understanding of cone dystrophy associated with GUCY2D mutation.

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: Fundus imaging and scatter diagrams for ocular characteristics of COD patients carrying the GUCY2D mutation in this family.
Fig. 2: OCT confirmed various degrees of retinal atrophy in the macula in these family members.
Fig. 3: Electroretinography, Sanger sequencing and pedigree in this family.

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Prokofyeva E, Troeger E, Bernd A, Zrenner E. Visual acuity changes in cone and cone-rod dystrophies. Ophthalmic Physiol Opt. 2012;32:53–59.

    Article  PubMed  Google Scholar 

  3. Boulanger-Scemama E, Mohand-Said S, El Shamieh S, Demontant V, Condroyer C, Antonio A, et al., Phenotype analysis of retinal dystrophies in light of the underlying genetic defects: application to cone and cone-rod dystrophies. Int J Mol Sci. 2019;20:4854.

  4. Michaelides M, Hardcastle AJ, Hunt DM, Moore AT. Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis. Surv Ophthalmol. 2006;51:232–58.

    Article  PubMed  Google Scholar 

  5. Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M. Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy. Br J Ophthalmol. 2019;103:711–20.

  6. Toto L, Battaglia Parodi M, D’Aloisio R, Mercuri S, Senatore A, Di Antonio L, et al. Cone dystrophies: an optical coherence tomography angiography study. J Clin Med. 2020;9:1500.

  7. Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, et al. Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. Mol Vis. 2016;22:150–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Watson CM, El-Asrag M, Parry DA, Morgan JE, Logan CV, Carr IM, et al. Mutation screening of retinal dystrophy patients by targeted capture from tagged pooled DNAs and next generation sequencing. PloS one. 2014;9:e104281.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kitiratschky VB, Wilke R, Renner AB, Kellner U, Vadala M, Birch DG, et al. Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Invest Ophthalmol Vis Sci. 2008;49:5015–23.

    Article  PubMed  Google Scholar 

  10. Dizhoor AM, Olshevskaya EV, Peshenko IV. The R838S mutation in retinal guanylyl cyclase 1 (RetGC1) alters calcium sensitivity of cGMP synthesis in the retina and causes blindness in transgenic mice. J Biol Chem. 2016;291:24504–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sato S, Peshenko IV, Olshevskaya EV, Kefalov VJ, Dizhoor AM, Cone-Rod GUCY2D. Dystrophy-6 is a “phototransduction disease” triggered by abnormal calcium feedback on retinal membrane guanylyl cyclase 1. J Neurosci. 2018;38:2990–3000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hughes AE, Meng W, Lotery AJ, Bradley DT. A novel GUCY2D mutation, V933A, causes central areolar choroidal dystrophy. Invest Ophthalmol Vis Sci. 2012;53:4748–53.

    Article  CAS  PubMed  Google Scholar 

  13. Sun Z, Wu S, Zhu T, Li H, Wei X, Du H, et al. Variants at codon 838 in the GUCY2D gene result in different phenotypes of cone rod dystrophy. Ophthalmic Genet. 2020;41:548–55.

    Article  CAS  PubMed  Google Scholar 

  14. Sharon D, Wimberg H, Kinarty Y, Koch KW. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D. Prog retinal eye Res. 2018;63:69–91.

    Article  CAS  Google Scholar 

  15. Hosono K, Harada Y, Kurata K, Hikoya A, Sato M, Minoshima S, et al. Novel GUCY2D gene mutations in japanese male twins with leber congenital amaurosis. J Ophthalmol. 2015;2015:693468.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stunkel ML, Brodie SE, Cideciyan AV, Pfeifer WL, Kennedy EL, Stone EM, et al. Expanded retinal disease spectrum associated with autosomal recessive mutations in GUCY2D. Am J Ophthalmol. 2018;190:58–68.

    Article  CAS  PubMed  Google Scholar 

  17. Song J, Smaoui N, Ayyagari R, Stiles D, Benhamed S, MacDonald IM, et al. High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci. 2011;52:9053–60.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu X, Tao T, Zhao L, Li G, Yang L. Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non-syndromic inherited retinal dystrophies. Clin Exp Ophthalmol. 2021;49(1):46–59.

    Article  PubMed  Google Scholar 

  19. Collery RF, Cederlund ML, Kennedy BN. Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology. Exp eye Res. 2013;108:120–8.

    Article  CAS  PubMed  Google Scholar 

  20. Wilkie SE, Newbold RJ, Deery E, Walker CE, Stinton I, Ramamurthy V, et al. Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy. Hum Mol Genet. 2000;9:3065–73.

    Article  CAS  PubMed  Google Scholar 

  21. Garcia-Hoyos M, Auz-Alexandre CL, Almoguera B, Cantalapiedra D, Riveiro-Alvarez R, Lopez-Martinez MA, et al. Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish families with autosomal dominant cone, cone-rod, and macular dystrophies. Mol Vis. 2011;17:1103–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Perrault I, Rozet JM, Gerber S, Kelsell RE, Souied E, Cabot A, et al. A retGC-1 mutation in autosomal dominant cone-rod dystrophy. Am J Hum Genet. 1998;63:651–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Payne AM, Morris AG, Downes SM, Johnson S, Bird AC, Moore AT, et al. Clustering and frequency of mutations in the retinal guanylate cyclase (GUCY2D) gene in patients with dominant cone-rod dystrophies. J Med Genet. 2001;38:611–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith M, Whittock N, Searle A, Croft M, Brewer C, Cole M. Phenotype of autosomal dominant cone-rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1. Eye. 2007;21:1220–5.

    Article  CAS  PubMed  Google Scholar 

  25. Van Ghelue M, Eriksen HL, Ponjavic V, Fagerheim T, Andreasson S, Forsman-Semb K, et al. Autosomal dominant cone-rod dystrophy due to a missense mutation (R838C) in the guanylate cyclase 2D gene (GUCY2D) with preserved rod function in one branch of the family. Ophthalmic Genet. 2000;21:197–209.

    Article  PubMed  Google Scholar 

  26. Lima LH, Sallum JM, Spaide RF. Outer retina analysis by optical coherence tomography in cone-rod dystrophy patients. Retina. 2013;33:1877–80.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank this family for participating in our study.

Funding

This work was financially supported by The Project of National Key Research and Development (No. 2018YFC1106103) to MZ and Post-Doctor Research Project, West China Hospital, Sichuan University (No.2021HXBH030), Natural Science Foundation of Sichuan Province (No. 2022NSFSC1285) to XR.

Author information

Author notes

  1. These authors contributed equally: Yunxia Gao, Xiang Ren.

Authors and Affiliations

  1. Department of Ophthalmology, Ophthalmic Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China

    Yunxia Gao, Xiang Ren, Hong Lin, Kang Li, Xiaoyue Wang, Zhibing Zeng, Ruijin Ran, Yunhan Tao, Yu Lin, Xiangyu Fu & Ming Zhang

  2. Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy; West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China

    Xiang Ren, Lirong Xiao, Yu Lin, Xiangyu Fu & Naihong Yan

  3. Department of Ophthalmology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciencies, 100730, Beijing, PR China

    Kang Li

  4. Minda Hospital of Hubei Minzu University, Enshi, PR China

    Ruijin Ran

Authors
  1. Yunxia Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiang Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lirong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoyue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhibing Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ruijin Ran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yunhan Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yu Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiangyu Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Naihong Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YG, and MZ designed the study, directed the project, and interpreted the data. KL, LX, HL, ZZ, XW, RR, YT and YG performed the experiments. NY provided guidance for this project. XR wrote the paper, and YL, XF, NY, and MZ contributed to editing. All authors contributed to the paper and approved the submitted version.

Corresponding authors

Correspondence to Naihong Yan or Ming Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Gao, Y., Ren, X., Lin, H. et al. Phenotypic characterization of autosomal dominant progressive cone dystrophies associated with a heterozygous variant c.2512C>T of GUCY2D gene in a large kindred. Eye 37, 2461–2469 (2023). https://doi.org/10.1038/s41433-022-02355-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41433-022-02355-1

Search

Advanced search

Quick links