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

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

doi:10.1038/s42003-021-02185-z

Cited by 24 publications

(36 citation statements)

References 134 publications

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“…Another GWAS found GJD2 to associate with refractive error [100]. A recent study showed that mutants in Exon 1 of GJD2 homologs in zebrafish induced a refractive error, consistent with the results of the human GWAS [101].…”

Section: Association Studies On Refractive Errorsupporting

confidence: 65%

Myopia Genetics and Heredity

Wang

Zhang

et al. 2022

Children

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Myopia is the most common eye condition leading to visual impairment and is greatly influenced by genetics. Over the last two decades, more than 400 associated gene loci have been mapped for myopia and refractive errors via family linkage analyses, candidate gene studies, genome-wide association studies (GWAS), and next-generation sequencing (NGS). Lifestyle factors, such as excessive near work and short outdoor time, are the primary external factors affecting myopia onset and progression. Notably, besides becoming a global health issue, myopia is more prevalent and severe among East Asians than among Caucasians, especially individuals of Chinese, Japanese, and Korean ancestry. Myopia, especially high myopia, can be serious in consequences. The etiology of high myopia is complex. Prediction for progression of myopia to high myopia can help with prevention and early interventions. Prediction models are thus warranted for risk stratification. There have been vigorous investigations on molecular genetics and lifestyle factors to establish polygenic risk estimations for myopia. However, genes causing myopia have to be identified in order to shed light on pathogenesis and pathway mechanisms. This report aims to examine current evidence regarding (1) the genetic architecture of myopia; (2) currently associated myopia loci identified from the OMIM database, genetic association studies, and NGS studies; (3) gene-environment interactions; and (4) the prediction of myopia via polygenic risk scores (PRSs). The report also discusses various perspectives on myopia genetics and heredity.

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Section: Association Studies On Refractive Errorsupporting

confidence: 65%

Myopia Genetics and Heredity

Wang

Zhang

et al. 2022

Children

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“…A custom MATLAB script was used for the analysis of the ocular components and total axial length, as described previously. 21 The dimensions of the ocular components were corrected for the refractive index of each ocular component: the cornea 1.33, 22 – 24 the lens (gradient refractive index) 1.40, 22 – 27 the anterior and vitreous chamber 1.34, and the retina 1.38. 24 , 28 , 29 Examiners were not masked to the genotype of the fish.…”

Section: Methodsmentioning

confidence: 99%

“…The slope of the brightness gradient was converted into refractive error by calibrating the system with ophthalmic lenses as described elsewhere. 21 Further details of this protocol can be found in Supplementary Materials (Protocol 2) .…”

Section: Methodsmentioning

confidence: 99%

Zebrafish: An In Vivo Screening Model to Study Ocular Phenotypes

Quint

Tadema

Crins

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose To establish a set of assays that allow the in vivo screening of candidate genes for ocular diseases in zebrafish, with an emphasis on refractive error. Methods Our pipeline includes the most relevant ocular screening measurements to assess (1) ocular biometry using spectral domain optical coherence tomography, (2) refractive status using an eccentric photorefractor, (3) intraocular pressure by tonometry, and (4) optokinetic response to study visual capability in zebrafish. To validate our pipeline and to demonstrate the potential of zebrafish as a valid animal model, we chose two well-characterized genes with an ocular phenotype ( PRSS56 and FBN1 ) and generated two mutant zebrafish lines ( prss56 and fbn1 ). Mutant fish were assessed at 2, 4, and 6 months after fertilization. Results With the proposed phenotyping pipeline, we showed that ocular biometry, refractive status, intraocular pressure, and visual function can be studied in zebrafish. In the prss56 mutant, the pipeline revealed a dramatic decrease in axial length, mainly owing to a decreased vitreous chamber depth, whereas in the fbn1 mutant, ectopia lentis was the most distinctive ocular phenotype observed. Tonometry in both mutant lines showed an increase in intraocular pressure. Conclusions The proposed pipeline was applied successfully in zebrafish and can be used for future genetic screenings of candidate genes. While validating our pipeline, we found a close resemblance between the ocular manifestations in the zebrafish mutants and patients harboring mutations in PRSS56 and FBN1 . Our results support the validity of our pipeline and highlight the potential of zebrafish as an animal model for in vivo screening of candidate genes for ocular diseases.

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“…Challenges applicable to both animal models include absence of a fovea, the limited visual acuity, the lack of accommodative reflex, and the small eye size. Even though hyperopic refractions have been reported for both mice and zebrafish, 153 , 154 studying the relative differences between wildtype and knockout animals will provide an indication of the relation between axial length changes and refractive error. Therefore, assessment of ocular biometry (i.e.…”

Section: Gjd2 (Cx36) In Animal Modelsmentioning

confidence: 99%

“…Depletion of gjd2a (cx35.5) leads to hyperopia and electrophysiological changes in the retina and a lack of gjd2b (cx35.1) leads to nuclear cataract and triggered axial elongation. 154 …”

Section: Gjd2 (Cx36) In Animal Modelsmentioning

confidence: 99%

The Role of GJD2(Cx36) in Refractive Error Development

Sande

Haarman

Quint

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Refractive errors are common eye disorders characterized by a mismatch between the focal power of the eye and its axial length. An increased axial length is a common cause of the refractive error myopia (nearsightedness). The substantial increase in myopia prevalence over the last decades has raised public health concerns because myopia can lead to severe ocular complications later in life. Genomewide association studies (GWAS) have made considerable contributions to the understanding of the genetic architecture of refractive errors. Among the hundreds of genetic variants identified, common variants near the gap junction delta-2 ( GJD2 ) gene have consistently been reported as one of the top hits. GJD2 encodes the connexin 36 (Cx36) protein, which forms gap junction channels and is highly expressed in the neural retina. In this review, we provide current evidence that links GJD2 (Cx36) to the development of myopia. We summarize the gap junctional communication in the eye and the specific role of GJD2 (Cx36) in retinal processing of visual signals. Finally, we discuss the pathways involving dopamine and gap junction phosphorylation and coupling as potential mechanisms that may explain the role of GJD2 (Cx36) in refractive error development.

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

Cited by 24 publications

References 134 publications

Myopia Genetics and Heredity

Myopia Genetics and Heredity

Zebrafish: An In Vivo Screening Model to Study Ocular Phenotypes

The Role of GJD2(Cx36) in Refractive Error Development

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