title: Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, UCL, London, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Osborne
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Susan
authors.initials: S
authors.lastname: Gribble
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.forename: Katrina
authors.initials: K
authors.lastname: Prescott
authors.forename: J Richard O
authors.initials: JR
authors.lastname: Collin
authors.forename: Tomas
authors.initials: T
authors.lastname: Fitzgerald
authors.forename: David
authors.initials: D
authors.lastname: Robinson
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Carter
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Ragge
mesh_terms: D000328:Adult; D000818:Animals; D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics; D002675:Child, Preschool; D005123:Eye / Q000196:embryology*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D012160:Retina / Q000002:abnormalities*; D050656:Transcription Factor AP-2 / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D029961:Zebrafish Proteins; C493676:tfap2a protein, zebrafish
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