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CHD7, the gene mutated in CHARGE syndrome,regulates genes involved in neural crest cell guidance |
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| Authors: | Yvonne Schulz Peter Wehner Lennart Opitz Gabriela Salinas-Riester Ernie M H F Bongers Conny M A van Ravenswaaij-Arts Josephine Wincent Jacqueline Schoumans Jürgen Kohlhase Annette Borchers Silke Pauli |
| Institution: | 1. Institute of Human Genetics, University Medical Center G?ttingen, Heinrich-Düker-Weg 12, 37073, G?ttingen, Germany 2. Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), GZMB, University of G?ttingen, 37077, G?ttingen, Germany 4. Department of Developmental Biochemistry, University Medical Center G?ttingen, 37077, G?ttingen, Germany 5. Department of Human Genetics, Radboud University Nijmegen Medical Center, 6500 HB, Nijmegen, The Netherlands 6. Department of Genetics, University Medical Centre Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands 7. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden 8. Cancer Cytogenetic Unit, Department of Medical Genetics, University Hospital of Lausanne, 1011, Lausanne, Switzerland 9. Center for Human Genetics, 79100, Freiburg, Germany 3. Department of Biology, Molecular Embryology, Philipps-University Marburg, 35043, Marburg, Germany |
| Abstract: | Heterozygous loss of function mutations in CHD7 (chromodomain helicase DNA-binding protein 7) lead to CHARGE syndrome, a complex developmental disorder affecting craniofacial structures, cranial nerves and several organ systems. Recently, it was demonstrated that CHD7 is essential for the formation of multipotent migratory neural crest cells, which migrate from the neural tube to many regions of the embryo, where they differentiate into various tissues including craniofacial and heart structures. So far, only few CHD7 target genes involved in neural crest cell development have been identified and the role of CHD7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown. Therefore, we undertook a genome-wide microarray expression analysis on wild-type and CHD7 deficient (Chd7 Whi/+ and Chd7 Whi/Whi ) mouse embryos at day 9.5, a time point of neural crest cell migration. We identified 98 differentially expressed genes between wild-type and Chd7 Whi/Whi embryos. Interestingly, many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors. By performing knockdown experiments for Chd7 in Xenopus laevis embryos, we found abnormalities in the expression pattern of Sema3a, a protein involved in the pathogenesis of Kallmann syndrome, in vivo. In addition, we detected non-synonymous SEMA3A variations in 3 out of 45 CHD7-negative CHARGE patients. In summary, we discovered for the first time that Chd7 regulates genes involved in neural crest cell guidance, demonstrating a new aspect in the pathogenesis of CHARGE syndrome. Furthermore, we showed for Sema3a a conserved regulatory mechanism across different species, highlighting its significance during development. Although we postulated that the non-synonymous SEMA3A variants which we found in CHD7-negative CHARGE patients alone are not sufficient to produce the phenotype, we suggest an important modifier role for SEMA3A in the pathogenesis of this multiple malformation syndrome. |
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