Clinical Presentation and the Presence of Hearing Impairment in Branchio-Oculo-Facial Syndrome: A New Mutation in the TFAP2A Gene

Thomeer, Hans G. X. M.; Crins, T. T. H.; Kamsteeg, Erik Jan; Buijsman, Wendy; Cruysberg, J.R.M.; Knoers, Nine V A M; Cremers, C.W.R.J.

doi:10.1177/000348941011901204

Cited by 9 publications

(4 citation statements)

References 23 publications

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“…Milunsky et al [2011] studied 30 families, including one family with a deletion, reporting that every proband had some form of cleft lip or philtrum irregularity, with or without cleft palate. This finding is consistent with additional BOF syndrome patients described most recently by Thomeer et al [2010] and Galliani et al [2012]. The exception remains the original deletion family described by Milunsky et al [2008].…”

Section: To the Editorsupporting

confidence: 91%

6p.24 microdeletion involving TFAP2A without classic features of branchio‐oculo‐facial syndrome

LeBlanc

Barnett

2013

American J of Med Genetics Pt A

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Section: To the Editorsupporting

confidence: 91%

6p.24 microdeletion involving TFAP2A without classic features of branchio‐oculo‐facial syndrome

LeBlanc

Barnett

2013

American J of Med Genetics Pt A

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“…BOFS is a dominantly inherited human birth defect that is characterized by multiple abnormalities affecting the face, eyes and neck (7,20). Genetic mapping and sequence analyses have demonstrated that BOFS is associated with more than 25 different mutations affecting TFAP2A, the human gene encoding AP-2a (6,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Some of these mutations are large chromosomal deletions or frame-shifts that would be predicted to eliminate protein function from the affected allele.…”

Section: Discussionmentioning

confidence: 99%

“…1 and (30 -32)]. Within this basic region, 24 different BOFS mutations have been identified (6,7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Sixteen residues have missense mutations, and of these the amino acids at L218, R237, R254 and R255 can exhibit changes to two or three different amino acids (see Supplementary Material, Table S1).…”

Section: Reduced Transcriptional Activity Of Bofs-associated Ap-2a Mutantsmentioning

confidence: 99%

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

Sheridan

Williams

2013

Human Molecular Genetics

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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.

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“…Point mutations or insertions/deletions in the conserved dna-binding domain in aP-2α, encoded by exons 4 and 5, cause the majority of branchio-oculo-facial syndrome (BoFS) cases (8). BoFS is associated with >25 different mutations in aP-2α (9)(10)(11)(12). Therefore, aP-2α mutants have been associated with certain developmental abnormalities.…”

Section: Introductionmentioning

confidence: 99%

KCTD1 mutants in scalp‑ear‑nipple syndrome and AP‑2α P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/β‑catenin signaling

Chen

Yang

et al. 2020

Mol Med Rep

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Potassium-channel tetramerization-domaincontaining 1 (KcTd1) mutations are reported to result in scalp-ear-nipple syndrome. These mutations occur in the conserved broad-complex, tramtrack and bric a brac domain, which is associated with inhibited transcriptional activity. However, the mechanisms of KcTd1 mutants have not previously been elucidated; thus, the present study aimed to investigate whether KcTd1 mutants affect their interaction with transcription factor aP-2α and their regulation of the Wnt pathway. results from the present study demonstrated that none of the ten KcTd1 mutants had an inhibitory effect on the transcriptional activity of aP-2α. co-immunoprecipitation assays demonstrated that certain mutants exhibited changeable localization compared with the nuclear localization of wild-type KcTd1, but no KcTd1 mutant interacted with aP-2α. almost all KcTd1 mutants, except KcTd1 a30e and H33Q, exhibited differential inhibitory effects on regulating ToPFlaSH luciferase reporter activity. in addition, the interaction region of KcTd1 to the PY motif (amino acids 59-62) in aP-2α was identified. KcTd1 exhibited no suppressive effects on the transcriptional activity of the aP-2α P59a mutant, resulting in char syndrome, a genetic disorder characterized by a distinctive facial appearance, heart defect and hand abnormalities, by altered protein cellular localization that abolished protein interactions. However, the P59a, P60a, P61r and 4a aP-2α mutants inhibited ToPFlaSH reporter activity. Moreover, aP-2α and KcTd1 inhibited β-catenin expression levels and SW480 cell viability. The present study thus identified a putative mechanism of disease-related KcTd1 mutants and aP-2α mutants by disrupting their interaction with the wildtype proteins aP-2α and KCTD1 and influencing the regulation of the Wnt/β-catenin pathway.

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Clinical Presentation and the Presence of Hearing Impairment in Branchio-Oculo-Facial Syndrome: A New Mutation in the TFAP2A Gene

Cited by 9 publications

References 23 publications

6p.24 microdeletion involving TFAP2A without classic features of branchio‐oculo‐facial syndrome

6p.24 microdeletion involving TFAP2A without classic features of branchio‐oculo‐facial syndrome

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

KCTD1 mutants in scalp‑ear‑nipple syndrome and AP‑2α P59A in Char syndrome reciprocally abrogate their interactions, but can regulate Wnt/β‑catenin signaling

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