A Clinical and Molecular Analysis of Branchio‐Oculo‐Facial Syndrome Patients in Russia Revealed New Mutations in TFAP2A

Abstract

SummaryBranchio-oculo-facial syndrome (BOFS, OMIM# 113620) is a rare autosomal dominant disorder characterised by branchial cleft sinus defects, ocular anomalies and facial dysmorphisms, including lip or palate cleft or pseudocleft, and is associated with mutations in the TFAP2A gene. Here, we performed clinical analysis and mutation diagnostics in seven BOFS patients in Russia. The phenotypic presentation of BOFS observed in three patients showed high heterogeneity, including variation in its main clinical manifestations (linear loci of cervical cutaneous aplasia, ocular anomalies and orofacial cleft). In certain other cases, isolated ocular anomalies, or an orofacial cleft with accessory BOFS symptoms, were observed. In five BOFS patients, conductive hearing loss was diagnosed. Direct sequencing of the coding region of the TFAP2A gene revealed missense mutations in four BOFS patients. One patient was observed to have a previously described mutation (p.Arg251Gly), while three patients from two families were found to have novel mutations: p.Arg213Ser and p.Val210Asp. These novel mutations were not present in healthy members of the same family and therefore should be classified as de novo.

Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes

“…44 Furthermore, mutations in TFAP2A cause the branchio-oculo-facial syndrome, which is a rare autosomal dominant birth defect. 45 According to our results, we can presume that a lower folate exposure at the time of conception increases methylation at the promoter of TFAP2A, repressing its expression. Therefore, in profound folate deficient individuals this mechanism may perhaps lead to defects in neural tube development without any changes in DNA sequence.…”

“…Two of the top associated sites were located at or near the promoter regions of the neuro-facial developmental genes TFAP2A and OTX2, which are implicated in neural crest development and are responsible for neuro-facial birth defects when mutated in the germline. [44][45][46] This suggests a potential mechanism whereby folate may affect susceptibility to neural tube defects via its impact on the function of these genes. OTX2 has also been involved in medulloblastoma development.…”

Dual control of pcdh8l/PCNS expression and function in Xenopus laevis neural crest cells by adam13/33 via the transcription factors tfap2α and arid3a

“…For adam13, we have identified a physical interaction with importin β1, which is known to mediate transport of proteins that do not harbor a canonical nuclear localization signal (Alfandari ms/ms unpublished). Given the essential and conserved role of tfap2α in craniofacial development ( de Crozé et al, 2011 ; Hoffman et al, 2007 ; Luo et al, 2003 ; Martinelli et al, 2011 ; Meshcheryakova et al, 2015 ; Van Otterloo et al, 2012 ; Hong et al, 2014 ), as well as its ability to reduce the proliferation and migration of multiple cancer cells including those derived from neural crest cells ( Su et al, 2014 ; Li et al, 2010 ; Bennett et al, 2009 ; Orso et al, 2007 ), it will be essential to study the potential regulation of tfap2α by human ADAM proteins. Our preliminary results show that mouse adam33 and adam12 are also able to induce the tfap2α reporter when transfected in Hek293T cells even if less efficiently than adam13 or adam19 while Xenopus adam9, 10 and 11 do not (data not shown).…”

“…Among those the transcription factor tfap2α is one of the earliest and most conserved factors that controls the fate of neural border cells and later neural crest cells ( de Croze et al, 2011 ). While loss of tfap2α in all vertebrates tested leads to craniofacial defects, mutations in the tfap2α gene in humans are associated with the Branchiooculofacial Syndrome highlighting the importance of this gene for craniofacial development and neural crest cell biology throughout evolution ( Hoffman et al, 2007 ; Luo et al, 2003 ; Martinelli et al, 2011 ; Meshcheryakova et al, 2015 ; Van Otterloo et al, 2012 ).…”

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 ].…”