Loss of Gap Junction Delta-2 (GJD2) gene orthologs leads to refractive error in zebrafish

Wim H. Quint*, Kirke C.D. Tadema, Erik de Vrieze, Rachel M. Lukowicz, Sanne Broekman, Beerend H.J. Winkelman, Melanie Hoevenaars, H. Martijn de Gruiter, Erwin van Wijk, Frank Schaeffel, Magda Meester-Smoor, Adam C. Miller, Rob Willemsen, Caroline C.W. Klaver, Adriana I. Iglesias*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)


Myopia is the most common developmental disorder of juvenile eyes, and it has become an increasing cause of severe visual impairment. The GJD2 locus has been consistently associated with myopia in multiple independent genome-wide association studies. However, despite the strong genetic evidence, little is known about the functional role of GJD2 in refractive error development. Here, we find that depletion of gjd2a (Cx35.5) or gjd2b (Cx35.1) orthologs in zebrafish, cause changes in the biometry and refractive status of the eye. Our immunohistological and scRNA sequencing studies show that Cx35.5 (gjd2a) is a retinal connexin and its depletion leads to hyperopia and electrophysiological changes in the retina. These findings support a role for Cx35.5 (gjd2a) in the regulation of ocular biometry. Cx35.1 (gjd2b) has previously been identified in the retina, however, we found an additional lenticular role. Lack of Cx35.1 (gjd2b) led to a nuclear cataract that triggered axial elongation. Our results provide functional evidence of a link between gjd2 and refractive error.

Original languageEnglish
Article number676
JournalCommunications Biology
Issue number1
Publication statusPublished - 3 Jun 2021

Bibliographical note

Funding Information:
We would like to thank Prof. Brian A. Link (Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin) for sharing the lrp2mw1 mutant fish, Prof. John O’Brien (Ruiz Department Of Ophthalmology & Visual Science, McGovern Medical School) for sharing his expertise on retinal connexins, and Prof. Maarten Kamermans (Netherlands Institute for Neuroscience) for sharing his expertise in retina and zebrafish. Also, we thank Johan Crins, Nina Kokke, Lotte Martens, Ewoud Ruighaver, and Joanna Świer-kowska for their technical support. Funding for this work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Program (grant 648268) and the Netherlands Organization for Scientific Research (NWO, grant 91815655 and VidW.1154.18.046) and Prof Dr. Henkes Stichting. This work was supported by the following foundations: Glaucoomfonds and Landelijke Stichting voor Blinden en Slechtzienden (LSBS) that contributed through UitZicht (project 2018–29). The funding organizations had no role in the design or conduct of this research. They provided unrestricted grants. This work was also supported by the NIH National Institute of General Medical Sciences, Genetics Training Grant T32GM007413

Funding Information:
to R.M.L., and the NIH Office of the Director R24OD026591 and the NIH National Institute of Neurological Disorders and Stroke R01NS105758 to A.C.M.

Publisher Copyright:
© 2021, The Author(s).


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