Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2α DNA-binding domain

Abstract

Multiple lines of evidence indicate that the AP-2 transcription factor family has an important regulatory function in human craniofacial development. Notably, mutations in TFAP2A, the gene encoding AP-2α, have been identified in patients with Branchio-Oculo-Facial Syndrome (BOFS). BOFS is an autosomal-dominant trait that commonly presents with facial clefting, eye defects and branchial skin anomalies. Examination of multiple cases has suggested either simple haploinsufficiency or more complex genetic causes for BOFS, especially as the clinical manifestations are variable, with no clear genotype-phenotype correlation. Mutations occur throughout TFAP2A, but mostly within conserved sequences within the DNA contact domain of AP-2α. However, the consequences of the various mutations for AP-2α protein function have not been evaluated. Therefore, it remains unclear if all BOFS mutations result in similar changes to the AP-2α protein or if they each produce specific alterations that underlie the spectrum of phenotypes. Here, we have investigated the molecular consequences of the mutations that localize to the DNA-binding region. We show that although individual mutations have different effects on DNA binding, they all demonstrate significantly reduced transcriptional activities. Moreover, all mutant derivatives have an altered nuclear:cytoplasmic distribution compared with the predominantly nuclear localization of wild-type AP-2α and several can exert a dominant-negative activity on the wild-type AP-2α protein. Overall, our data suggest that the individual TFAP2A BOFS mutations can generate null, hypomorphic or antimorphic alleles and that these differences in activity, combined with a role for AP-2α in epigenetic events, may influence the resultant pathology and the phenotypic variability.

IRF6 and AP2A Interaction Regulates Epidermal Development

“…Additionally, mutations in TFAP2A can lead to branchio-oculo-facial syndrome (OMIM#113620). Like VWS and PPS, individuals with branchio-oculo-facial syndrome can have orofacial clefting, lip pits, and cutaneous abnormalities (Li et al, 2013;Milunsky et al, 2008;Stoetzel et al, 2009). Finally, mutations in TP63 can cause ectrodactyly, ectodermal dysplasia, and cleft (OMIM#604292), an autosomal dominant form of orofacial clefting (Celli et al, 1999).…”

Tfap2a-dependent changes in facial morphology result in clefting that can be ameliorated by a reduction inFgf8gene dosage

“…Specifically, we can employ geometric morphometrics to test the hypothesis that there are alterations in facial morphology that correlate with the development of orofacial clefting. In humans, TFAP2A is mutated in branchio-oculo-facial syndrome (BOFS) and regulates, or is regulated by, additional genes associated with orofacial clefting, including Irf6 , BCOR and p63 ( Fan et al, 2009 ; Ferretti et al, 2011 ; Gritli-Linde, 2010 ; Li et al, 2013a ; Milunsky et al, 2008 ; Rahimov et al, 2008 ; Stoetzel et al, 2009 ; Thomason et al, 2010 ; Wang et al, 2013 ). Therefore, our findings are directly relevant to the genetic underpinnings of human CL/P and provide mechanistic insight into how such pathology can be modified.…”

The Transcriptional Network Structure of a Myeloid Cell: A Computational Approach

“…This transcription factor is known as a tumor suppressor gene. Decreased expression of this gene has been related to many neoplasms [ 27 – 29 ], as well as other diseases, such as the brachio-oculo-facial syndrome [ 30 , 31 ].…”