Molecular Pathogenesis
TFAP2A is a retinoic acid-responsive member of the AP-2 family of transcription factors that regulate gene expression during embryogenesis of the eye, ear, face, body wall, limbs, and neural tube [Schorle et al 1996, Zhang et al 1996, Ahituv et al 2004, Nelson & Williams 2004].
Gene structure.
TFAP2A contains eight coding exons (reference sequence NM_003220.2, NM_001042425.1, NM_001032280.2). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Pathogenic variants within TFAP2A or deletion of the entire gene result in the branchiooculofacial (BOF) syndrome. Milunsky et al [2008] described a familial whole-gene deletion and four de novo missense variants in simplex cases (i.e., a single occurrence in the family) that resulted in BOFS. Additional pathogenic variants and familial deletions have now been described [Gestri et al 2009, Stoetzel et al 2009, Tekin et al 2009, Reiber et al 2010, Aliferis et al 2011, Frascari et al 2012, Galliani et al 2012, LeBlanc et al 2013, Murray et al 2013, Günes et al 2014, Meshcheryakova et al 2015, Titheradge et al 2015, Xiong et al 2015, Yi et al 2016].
Although the pathogenic variants occur throughout the gene, a hot spot region in exons 6 and 7 that harbors missense variants in about 90% of probands/families with BOFS has been identified [Milunsky et al 2011].
Mosaicism has been detected in one family [Milunsky et al 2011].
The molecular spectrum in 30 families with 41 affected individuals with BOFS included heterozygous missense variants (28/30; 93%), one frameshift variant, and one whole-gene deletion [Milunsky et al 2011]. Tekin et al [2009] reported a complex TFAP2A allele (deletion of 18 and insertion of 6 nucleotides) between amino acids 276 and 281 in an individual with BOFS. More than 30 missense/nonsense pathogenic variants have now been described along with several small deletions/insertions and fewer than five whole-gene deletions.
Normal gene product. TFAP2A protein comprises 437 amino acids. It has a central basic DNA binding region, a carboxy terminus helix-span-helix motif that mediates dimerization, and an amino terminus that contains a transactivation domain [Eckert et al 2005]. The amino acids in the basic region of the DNA binding domain (exons 6 and 7) show high evolutionary conservation from Homo sapiens through Ciona intestinalis (transparent sea squirt) [Milunsky et al 2008].
In addition to its role in regulating gene expression during embryogenesis, TFAP2A is also involved in tumorigenesis with protein expression levels affecting cell transformation, tumor growth, metastasis, and survival [Jean et al 1998, Heimberger et al 2005, Orso et al 2007]. Numerous gene interactions likely underlie the variability in phenotype resulting from molecular defects involving TFAP2A. TFAP2A is known to be expressed in premigratory and migratory neural crest cells [Hilger-Eversheim et al 2000, Li & Cornell 2007] and is required for early morphogenesis of the lens [Gestri et al 2009].
Abnormal gene product. In humans, the described anomalies in BOFS appear to be related to pathogenic variants or deletions of TFAP2A leading to dysfunctional regulation especially during embryogenesis.
Loss or alteration of function of TFAP2A protein orthologs in zebrafish or mice result in facial clefting, limb anomalies, and defects of the eye, ear, body wall, neural tube, and heart outflow tract [Schorle et al 1996, Zhang et al 1996, Nottoli et al 1998, West-Mays et al 1999, Brewer et al 2002, Holzschuh et al 2003, Knight et al 2003, Ahituv et al 2004, Brewer et al 2004, Nelson & Williams 2004, Feng et al 2008].
A study by Gestri et al [2009] of the role of TFAP2A pathogenic variants in zebrafish eye morphogenesis revealed an association with a multitude of ocular pathologies. In addition, the pathogenic variants compromised the gene function, thereby sensitizing the developing eye to deleterious pathogenic variants of other genes including bmp4 and tcf711a [Gestri et al 2009].
Damberg [2005] found that the AP-2 family may be involved in the regulation of the monoaminergic systems in the adult brain, resulting in neuropsychiatric disorders.
Brewer et al [2004] noted that surviving mutated Tcfap2a mice have craniofacial anomalies, abnormal middle ear development, and defects in pigmentation.
Li et al [2013] demonstrated that several pathogenic variants in the DNA binding domain can have dominant-negative activity on wild type AP-2α protein. Hence, differences in activity due to null, hypomorphic, or antimorphic alleles may lead to the phenotypic variability characteristic of BOFS