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PMID:19685247

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Citation

Gestri, G, Osborne, RJ, Wyatt, AW, Gerrelli, D, Gribble, S, Stewart, H, Fryer, A, Bunyan, DJ, Prescott, K, Collin, JR, Fitzgerald, T, Robinson, D, Carter, NP, Wilson, SW and Ragge, NK (2009) Reduced TFAP2A function causes variable optic fissure closure and retinal defects and sensitizes eye development to mutations in other morphogenetic regulators. Hum. Genet. 126:791-803

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.

Links

PubMed PMC3083835 Online version:10.1007/s00439-009-0730-x

Keywords

Adult; Animals; Branchio-Oto-Renal Syndrome/genetics; Child, Preschool; Eye/embryology; Eye Abnormalities/genetics; Female; Gene Deletion; Humans; Infant; Male; Middle Aged; Morphogenesis/genetics; Mutation; Retina/abnormalities; Transcription Factor AP-2/genetics; Zebrafish; Zebrafish Proteins/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8QRQ5

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:A0A2R8QRQ5

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:A0A2R8RSI4

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:A0A2R8RSI4

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:F1QUT4

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:F1QUT4

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:F1QUT5

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:F1QUT5

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6NYI3

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6NYI3

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6P975

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6P975

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6YA67

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q6YA67

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q8UVE5

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q8UVE5

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q8UVE6

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete

DANRE:Q8UVE6

involved_in

GO:0060041: retina development in camera-type eye

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060927-2

P

Seeded From UniProt

complete


See also

References

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