Molecular and developmental mechanisms of anterior segment dysgenesis

Sowden, Jane C.

doi:10.1038/sj.eye.6702852

Cited by 132 publications

(104 citation statements)

References 49 publications

(53 reference statements)

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“…41,42 In humans, mutation of the forkhead C1 (FOXC1) transcription factor gene results in a spectrum of anterior segment dysgenesis phenotypes, including glaucoma in some individuals. 43 Zebrafish foxc1 expression is limited to the anterior segment and periocular mesenchyme, 44 and has been implicated in the regulation of factors that mediate responses to oxidative stress and suppression of apoptosis in cells involved in aqueous humour dynamics. 45 In addition, loss of foxC1 results in defects of the vascular basement membrane integrity indicating that genetic interactions between foxC1 and basement membrane components influence vascular stability which may impact glaucoma pathogenesis.…”

Section: Glaucomamentioning

confidence: 99%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

134

140

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Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.

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Section: Glaucomamentioning

confidence: 99%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

134

140

View full text Add to dashboard Cite

show abstract

“…In the eye, neural crest cells migrate to the developing anterior chamber of the eye forming the keratocytes and corneal endothelium, iris stroma cells, melanocytes, trabecular meshwork and juxtacanalicular tissue. 3,7,8 Developmental arrest that occurs late in gestation results in the neural crest cells being retained over parts of the iris and anterior chamber angle. 3 This affects the anatomy of the anterior chamber angle, eventually effecting aqueous drainage and causing glaucoma as observed in ARS.…”

Section: Embryology Of the Anterior Segmentmentioning

confidence: 99%

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

2009

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In association withAxenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations Axenfeld -Rieger syndrome (ARS) is a rare autosomal dominant disorder, which encompasses a range of congential malformations affecting the anterior segment of the eye. ARS shows genetic heterogeneity and mutations of the two genes, PITX2 and FOXC1, are known to be associated with the pathogenesis. There are several excellent reviews dealing with the complexity of the phenotype and genotype of ARS. In this study, we will attempt to give a brief review of the clinical features and the relevant diagnostic approaches, together with a detailed review of published PITX2 and FOXC1 mutations.

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“…Patients may also have systemic extraocular features including facial dysmorphism (maxillary hypoplasia, hypertelorism, telecanthus, prominent forehead), dental anomalies (hypodontia, microdontia), and/or redundant periumbilical skin. The condition is associated with raised intraocular pressure and an increased incidence of glaucoma affecting approximately 50% of patients has been reported [Idrees et al, 2006b;Sowden, 2007;Tumer and BachHolm, 2009].…”

Section: Introductionmentioning

confidence: 99%

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

et al. 2011

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Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with AxenfeldRieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR

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Molecular and developmental mechanisms of anterior segment dysgenesis

Cited by 132 publications

References 49 publications

The zebrafish eye—a paradigm for investigating human ocular genetics

The zebrafish eye—a paradigm for investigating human ocular genetics

Axenfeld–Rieger syndrome and spectrum of PITX2 and FOXC1 mutations

Digenic inheritance of mutations in FOXC1 and PITX2 : Correlating transcription factor function and axenfeld-rieger disease severity

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