TFAP2E is implicated in central nervous system, orofacial and maxillofacial anomalies.

Kalanithy JC, Mingardo E, Stegmann JD, Dhakar R, Dakal TC, Rosenfeld JA, Tan WH, Coury SA, Woerner AC, Sebastian J, Levy PA, Fleming LR, Waffenschmidt L, Lindenberg TT, Yilmaz Ö, Channab K, Babra BK, Christ A, Eiberger B, Hölzel S, Vidic C, Häberlein F, Ishorst N, Rodriguez-Gatica JE, Pezeshkpoor B, Kupczyk PA, Vanakker OM, Loddo S, Novelli A, Dentici ML, Becker A, Thiele H, Posey JE, Lupski JR, Hilger A, Reutter HM, Merz WM, Dworschak GC, Odermatt B (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Journal of Medical Genetics BMJ Publishing Group

Book Volume: 62

Pages Range: 126-137

Journal Issue: 2

DOI: 10.1136/jmg-2023-109799

Abstract

BACKGROUND: Previous studies in mouse, Xenopus and zebrafish embryos show strong tfap2e expression in progenitor cells of neuronal and neural crest tissues suggesting its involvement in neural crest specification. However, the role of human transcription factor activator protein 2 (TFAP2E) in human embryonic central nervous system (CNS), orofacial and maxillofacial development is unknown. METHODS: Through a collaborative work, exome survey was performed in families with congenital CNS, orofacial and maxillofacial anomalies. Exome variant prioritisation prompted TFAP2E gene for functional analysis in zebrafish embryos. Embryonic morphology and development were assessed after antisense morpholino (MO) knockdown (KD), CRISPR/Cas9 knockout and overexpression of tfap2e in fluorescent zebrafish reporter lines using in vivo microscopy. Computational structural protein modelling of the identified human variants was performed. RESULTS: In total, exome survey identified novel or ultra-rare heterozygous missense variants in TFAP2E in seven individuals from five independent families with predominantly CNS, orofacial and maxillofacial anomalies. One variant was found de novo and another variant segregated in an affected multiplex family. Protein modelling of the identified variants indicated potential distortion of TFAP2E in the transactivation or dimerisation domain. MO KD and CRISPR/Cas9 knockout of tfap2e in zebrafish revealed hydrocephalus and a significant reduction of brain volume, consistent with a microencephaly phenotype. Furthermore, mRNA overexpression of TFAP2E indicates dosage-sensitive phenotype expression. In addition, zebrafish showed orofacial and maxillofacial anomalies following tfap2e KD, recapitulating the human phenotype. CONCLUSION: Our human genetic data and analysis of Tfap2e manipulation in zebrafish indicate a potential role of TFAP2E in human CNS, orofacial and maxillofacial anomalies.

Authors with CRIS profile

Alina Hilger Department of Paediatrics and Adolescent Medicine

Additional Organisation(s)

Professur für seltene Nierenerkrankungen

Involved external institutions

Universitätsklinikum Bonn DE Germany (DE) Mohanlal Sukhadia University / University of Udaipur IN India (IN) Baylor Genetics US United States (USA) (US) Boston Children's Hospital US United States (USA) (US) University of Pittsburgh Medical Center (UPMC) US United States (USA) (US) Children’s Hospital at Montefiore US United States (USA) (US) Saint Luke's Health System US United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) University Hospital Ghent BE Belgium (BE) Ospedale Pediatrico Bambino Gesu IT Italy (IT) Universität zu Köln DE Germany (DE) Baylor College of Medicine US United States (USA) (US)

How to cite

APA:

Kalanithy, J.C., Mingardo, E., Stegmann, J.D., Dhakar, R., Dakal, T.C., Rosenfeld, J.A.,... Odermatt, B. (2025). TFAP2E is implicated in central nervous system, orofacial and maxillofacial anomalies. Journal of Medical Genetics, 62(2), 126-137. https://doi.org/10.1136/jmg-2023-109799

MLA:

Kalanithy, Jeshurun C., et al. "TFAP2E is implicated in central nervous system, orofacial and maxillofacial anomalies." Journal of Medical Genetics 62.2 (2025): 126-137.

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