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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

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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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We gratefully acknowledge the help of many colleagues especially Heather Stickney and Rodrigo Young for help with zebrafish experiments and discussions, Dr Angela Martin for research co-ordination, Shane Giles and Tara Hill (Agilent Technologies) for technical support and supplying oligonucleotide array probe scores, clinical staff and colleagues including Dr Alison Salt, Mr Yassir Abou-Rayyah, Professor Graham Holder, Ms Marie Restori, Mr James Innes, Ms Jo Allard for their support. We are particularly grateful to the patients and their families for their willing and enthusiastic participation in the study. This study was supported by a Telethon Fellowship (GG), MRC project grant and Wellcome Trust programme grant (SW), Wellcome Trust [grant number WT077008] (NPC, TF, and SG), a Senior Surgical Scientist Award from the Academy of Medical Sciences/Health Foundation (NR) and generous grants from VICTA (RO), Polak Trust and VICTA (AW). The MRC/Wellcome-funded Human Developmental Biology Resource provided human embryonic material.

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Correspondence to Nicola K. Ragge.

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G. Gestri and R. J. Osborne are joint first authors.

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Gestri, G., Osborne, R.J., Wyatt, A.W. et al. Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators. Hum Genet 126, 791 (2009). https://doi.org/10.1007/s00439-009-0730-x

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  • Ganglion Cell Layer
  • Neural Retina
  • Microphthalmia
  • Palatal Shelf
  • Postaxial Polydactyly