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      Ocular manifestations of branchio-oculo-facial syndrome: Report of a novel mutation and review of the literature

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          To report unusual ocular manifestations of branchio-oculo-facial syndrome (BOFS) caused by a novel mutation in activating enhancer binding protein 2 alpha ( TFAP2A).


          Full ophthalmological evaluation and direct sequencing of TFAP2A.


          A 10-year-old girl with unusual ocular manifestations of BOFS such as elliptical shaped microcornea and a novel de novo TFAP2A mutation was identified.


          This report expands the ocular phenotypic spectrum of BOFS and adds to the small number of reported TFAP2A mutations.

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          Most cited references 25

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          AP-2alpha transcription factor is required for early morphogenesis of the lens vesicle.

          AP-2 transcription factors are a family of retinoic acid-responsive genes, which are involved in complex morphogenetic processes. In the current study, we determine the requirement for AP-2alpha in early morphogenesis of the eye by examining the nature of the ocular defects in AP-2alpha null and chimeric mice. AP-2alpha null embryos exhibited ocular phenotypes ranging from a complete lack of eyes (anophthalmia) to defects in the developing lens involving a persistent adhesion of the lens to the overlying surface ectoderm. Two genes involved in lens development and differentiation, Pax6 and MIP26 were also misexpressed. AP-2alpha mutants also exhibited defects in the optic cup consisting of transdifferentiation of the dorsal retinal pigmented epithelium into neural retina and the absence of a defined ganglion cell layer. Newly generated chimeric embryos consisting of a population of AP-2alpha-/- and AP-2alpha+/+ cells exhibit ocular defects similar to those seen in the knockout embryos. Immunolocalization of AP-2 proteins (alpha, beta, and gamma) to the normal developing eye revealed both unique and overlapping expression patterns, with AP-2alpha expressed in a number of the ocular tissues that exhibited defects in the mutants, including the developing lens where AP-2alpha is uniquely expressed. Together these findings demonstrate a requirement for AP-2alpha in early morphogenesis of the eye. Copyright 1999 Academic Press.
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            Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators.

            Mutations in the transcription factor encoding TFAP2A gene underlie branchio-oculo-facial syndrome (BOFS), a rare dominant disorder characterized by distinctive craniofacial, ocular, ectodermal and renal anomalies. To elucidate the range of ocular phenotypes caused by mutations in TFAP2A, we took three approaches. First, we screened a cohort of 37 highly selected individuals with severe ocular anomalies plus variable defects associated with BOFS for mutations or deletions in TFAP2A. We identified one individual with a de novo TFAP2A four amino acid deletion, a second individual with two non-synonymous variations in an alternative splice isoform TFAP2A2, and a sibling-pair with a paternally inherited whole gene deletion with variable phenotypic expression. Second, we determined that TFAP2A is expressed in the lens, neural retina, nasal process, and epithelial lining of the oral cavity and palatal shelves of human and mouse embryos--sites consistent with the phenotype observed in patients with BOFS. Third, we used zebrafish to examine how partial abrogation of the fish ortholog of TFAP2A affects the penetrance and expressivity of ocular phenotypes due to mutations in genes encoding bmp4 or tcf7l1a. In both cases, we observed synthetic, enhanced ocular phenotypes including coloboma and anophthalmia when tfap2a is knocked down in embryos with bmp4 or tcf7l1a mutations. These results reveal that mutations in TFAP2A are associated with a wide range of eye phenotypes and that hypomorphic tfap2a mutations can increase the risk of developmental defects arising from mutations at other loci.
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              AP-2alpha knockout mice exhibit optic cup patterning defects and failure of optic stalk morphogenesis.

              Appropriate development of the retina and optic nerve requires that the forebrain-derived optic neuroepithelium undergoes a precisely coordinated sequence of patterning and morphogenetic events, processes which are highly influenced by signals from adjacent tissues. Our previous work has suggested that transcription factor activating protein-2 alpha (AP-2alpha; Tcfap2a) has a non-cell autonomous role in optic cup (OC) development; however, it remained unclear how OC abnormalities in AP-2alpha knockout (KO) mice arise at the morphological and molecular level. In this study, we show that patterning and morphogenetic defects in the AP-2alpha KO optic neuroepithelium begin at the optic vesicle stage. During subsequent OC formation, ectopic neural retina and optic stalk-like tissue replaced regions of retinal pigment epithelium. AP-2alpha KO eyes also displayed coloboma in the ventral retina, and a rare phenotype in which the optic stalk completely failed to extend, causing the OCs to be drawn inward to the midline. We detected evidence of increased sonic hedgehog signaling in the AP-2alpha KO forebrain neuroepithelium, which likely contributed to multiple aspects of the ocular phenotype, including expansion of PAX2-positive optic stalk-like tissue into the OC. Our data suggest that loss of AP-2alpha in multiple tissues in the craniofacial region leads to severe OC and optic stalk abnormalities by disturbing the tissue-tissue interactions required for ocular development. In view of recent data showing that mutations in human TFAP2A result in similar eye defects, the current findings demonstrate that AP-2alpha KO mice provide a valuable model for human ocular disease.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                08 May 2010
                : 16
                : 813-818
                [1 ]Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
                [2 ]Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
                [3 ]College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [4 ]Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
                [5 ]Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
                [6 ]Peadiatric Ophthalmology Division King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
                [7 ]Department of Pediatrics, University of Kentucky, Lexington, KY
                [8 ]Department of Pediatrics, King Khalid University Hospital and College of Medicine, Riyadh, Saudi Arabia
                [9 ]Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
                Author notes

                The first two authors contributed equally to this work and are considered as co-first authors.

                Correspondence to: Fowzan S. Alkuraya, M.D., Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC 03, PO Box 3354, Riyadh 11211, Saudi Arabia; Phone: +966 1 442 7875; FAX: +966 1 442 4585; email: falkuraya@ 123456kfshrc.edu.sa
                91 2010MOLVIS0091
                Copyright © 2010 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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