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

Autor:	Kalanithy JC; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany jkalanithy@uni-bonn.de.; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Mingardo E; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Stegmann JD; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Dhakar R; Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India., Dakal TC; Genome and Computational Biology Lab, Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India., Rosenfeld JA; Baylor Genetics Laboratories, Houston, Texas, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Tan WH; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA., Coury SA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.; Genomes2People Research Program, Division of Genetics, Department of Medicine, Mass General Brigham Inc, Boston, Massachusetts, USA., Woerner AC; Department of Pediatrics, Division of Genetic and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA., Sebastian J; Department of Pediatrics, Division of Genetic and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA., Levy PA; Department of Pediatrics, Children's Hospital at Montefiore, New York, New York, USA., Fleming LR; Genetics and Metabolic Clinic, St Luke's Health System, Boise, Idaho, USA., Waffenschmidt L; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Lindenberg TT; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany., Yilmaz Ö; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany., Channab K; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Babra BK; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany., Christ A; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Eiberger B; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany., Hölzel S; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Vidic C; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Häberlein F; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.; Institute of Pharmaceutical Biology, Molecular, Cellular, and Pharmacobiology Section, University of Bonn, Bonn, Germany., Ishorst N; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Rodriguez-Gatica JE; Clausius Institute of Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany., Pezeshkpoor B; Institute for Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany.; Center for Rare Diseases Bonn, University Hospital Bonn, Bonn, Germany., Kupczyk PA; Department of Diagnostic and Interventional Radiology, University Hospital Bonn, Bonn, Germany., Vanakker OM; Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium., Loddo S; Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Novelli A; Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Dentici ML; Medical Genetics Unit, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Becker A; Institute for Cellular Neurosciences II, University Hospital Bonn, Bonn, Germany., Thiele H; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Lupski JR; Molecular and Human Genetics; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Hilger AC; Research Center On Rare Kidney Diseases (RECORD), Erlangen University Hospital, Erlangen, Germany.; Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Reutter HM; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.; Department of Pediatric and Adolescent Medicine, Division Neonatology and Pediatric Intensive Care, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.; Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Merz WM; Department of Obstetrics and Prenatal Medicine, University Hospital Bonn, Bonn, Germany., Dworschak GC; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.; Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany., Odermatt B; Institute of Neuroanatomy, Medical Faculty, University of Bonn, Bonn, Germany.; Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, Bonn, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2024 Dec 23. Date of Electronic Publication: 2024 Dec 23.
DOI:	10.1136/jmg-2023-109799
Abstrakt:	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. Competing Interests: Competing interests: JRL has stock ownership in 23andMe, and is a member of the Scientific Advisory Board of Genome International, and an expert witness for Hawley-Troxell, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered at Baylor Genetics. All other authors declare no conflicts of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)
Databáze:	MEDLINE
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