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1. Targeting fibroblast growth factor receptors causes severe craniofacial malformations in zebrafish larvae

Author

Gebuijs, I.G.E., Wagener, F.A., Zethof, J, Carels, C.E., Hoff, J.W. Von den, and Metz, J.R.

Subjects
Animal Ecology and Physiology, Inhibitors, General Neuroscience, Craniofacial malformations, General Medicine, Development, General Biochemistry, Genetics and Molecular Biology, FGF signaling, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Organismal Animal Physiology, Cranial neural crest cells, General Agricultural and Biological Sciences, Zebrafish, FGFR mutation
Abstract

Background and Objective A key pathway controlling skeletal development is fibroblast growth factor (FGF) and FGF receptor (FGFR) signaling. Major regulatory functions of FGF signaling are chondrogenesis, endochondral and intramembranous bone development. In this study we focus on fgfr2, as mutations in this gene are found in patients with craniofacial malformations. The high degree of conservation between FGF signaling of human and zebrafish (Danio rerio) tempted us to investigate effects of the mutated fgfr2sa10729 allele in zebrafish on cartilage and bone formation. Methods We stained cartilage and bone in 5 days post fertilization (dpf) zebrafish larvae and compared mutants with wildtypes. We also determined the expression of genes related to these processes. We further investigated whether pharmacological blocking of all FGFRs with the inhibitor BGJ398, during 0–12 and 24–36 h post fertilization (hpf), affected craniofacial structure development at 5 dpf. Results We found only subtle differences in craniofacial morphology between wildtypes and mutants, likely because of receptor redundancy. After exposure to BGJ398, we found dose-dependent cartilage and bone malformations, with more severe defects in fish exposed during 0–12 hpf. These results suggest impairment of cranial neural crest cell survival and/or differentiation by FGFR inhibition. Compensatory reactions by upregulation of fgfr1a, fgfr1b, fgfr4, sp7 and dlx2a were found in the 0–12 hpf group, while in the 24–36 hpf group only upregulation of fgf3 was found together with downregulation of fgfr1a and fgfr2. Conclusions Pharmacological targeting of FGFR1-4 kinase signaling causes severe craniofacial malformations, whereas abrogation of FGFR2 kinase signaling alone does not induce craniofacial skeletal abnormalities. These findings enhance our understanding of the role of FGFRs in the etiology of craniofacial malformations.

Published
2022

2. Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

Author

Rooij, I.A.L.M. van, Ludwig, K.U., Welzenbach, J., Ishorst, N., Thonissen, M., Galesloot, T.E., Ongkosuwito, E.M., Berge, S.J., Aldhorae, K., Rojas-Martinez, A., Kiemeney, L.A., Vermeesch, J.R., Brunner, H.G., Roeleveld, N., Devriendt, K., Dormaar, T., Hens, G., Knapp, M., Carels, C.E., Mangold, E., Rooij, I.A.L.M. van, Ludwig, K.U., Welzenbach, J., Ishorst, N., Thonissen, M., Galesloot, T.E., Ongkosuwito, E.M., Berge, S.J., Aldhorae, K., Rojas-Martinez, A., Kiemeney, L.A., Vermeesch, J.R., Brunner, H.G., Roeleveld, N., Devriendt, K., Dormaar, T., Hens, G., Knapp, M., Carels, C.E., and Mangold, E.

Abstract

Contains fulltext : 215284.pdf (publisher's version ) (Open Access), Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 x 10(-7)). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

Published
2019

4. Effects of Remote Ischemic Preconditioning on Heme Oxygenase-1 Expression and Cutaneous Wound Repair

Author

Cremers, N.A.J., Wever, K.E., Wong, R.J., Rheden, R.E.M. van, Vermeij, E.A., Dam, G.M. van, Carels, C.E., Lundvig, D.M.S., Wagener, F.A., Cremers, N.A.J., Wever, K.E., Wong, R.J., Rheden, R.E.M. van, Vermeij, E.A., Dam, G.M. van, Carels, C.E., Lundvig, D.M.S., and Wagener, F.A.

Abstract

Contains fulltext : 169649.pdf (publisher's version ) (Open Access), Skin wounds may lead to scar formation and impaired functionality. Remote ischemic preconditioning (RIPC) can induce the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and protect against tissue injury. We aim to improve cutaneous wound repair by RIPC treatment via induction of HO-1. RIPC was applied to HO-1-luc transgenic mice and HO-1 promoter activity and mRNA expression in skin and several other organs were determined in real-time. In parallel, RIPC was applied directly or 24h prior to excisional wounding in mice to investigate the early and late protective effects of RIPC on cutaneous wound repair, respectively. HO-1 promoter activity was significantly induced on the dorsal side and locally in the kidneys following RIPC treatment. Next, we investigated the origin of this RIPC-induced HO-1 promoter activity and demonstrated increased mRNA in the ligated muscle, heart and kidneys, but not in the skin. RIPC did not change HO-1 mRNA and protein levels in the wound 7 days after cutaneous injury. Both early and late RIPC did not accelerate wound closure nor affect collagen deposition. RIPC induces HO-1 expression in several organs, but not the skin, and did not improve excisional wound repair, suggesting that the skin is insensitive to RIPC-mediated protection.

Published
2017

5. AGORA, a data- and biobank for birth defects and childhood cancer

Author

Rooij, I.A.L.M. van, Zanden, L.F.M. van der, Bongers, E.M., Renkema, K.Y., Wijers, C.H., Thonissen, M., Dokter, E.M., Marcelis, C.L., Blaauw, I. de, Wijnen, M.H.W.A., Hoogerbrugge, P.M., Bökkerink, J.P., Schreuder, M.F., Koster-Kamphuis, L., Cornelissen, E.A., Kapusta, L., Heijst, A.F.J. van, Liem, K.D., Gier, R.P. de, Kuijpers-Jagtman, A.M., Admiraal, R.J., Berge, S.J., Biezen, J.J. van der, Verdonck, A., Poorten, V. Van der, Hens, G., Roosenboom, J., Lilien, M.R., Jong, T.P. de, Broens, P., Wijnen, R., Brooks, A., Franke, B., Brunner, H.G., Carels, C.E., Knoers, N.V.A.M., Feitz, W.F., Roeleveld, N., Paediatric Surgery, Urology, Paediatric Urology, Pediatric Surgery, and Clinical Genetics

Subjects
Adult, Male, Databases, Factual, etiology, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], HYPOSPADIAS, Congenital Abnormalities, SDG 3 - Good Health and Well-being, Pregnancy, Risk Factors, Neoplasms, Surveys and Questionnaires, Journal Article, cancer, Humans, genetics, Child, Life Style, Biological Specimen Banks, RISK, ENVIRONMENT, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], congenital malformations, environment, risk factor, Metabolic Disorders Radboud Institute for Health Sciences [Radboudumc 6], Infant, Newborn, Infant, ASSOCIATION, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Case-Control Studies, Child, Preschool, Prenatal Exposure Delayed Effects, CONGENITAL ANORECTAL-MALFORMATIONS, Female, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 167851.pdf (Publisher’s version ) (Open Access) BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. (c) 2016 Wiley Periodicals, Inc.

Published
2016

6. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Author

Ockeloen, C.W., Khandelwal, K.D., Dreesen, K., Ludwig, K.U., Sullivan, R., Rooij, I.A van, Thonissen, M., Swinnen, S., Phan, M., Conte, F, Ishorst, N., Gilissen, C., Roa Fuentes, L., van de Vorst, M., Henkes, A., Steehouwer, M., van Beusekom, E., Bloemen, M., Vankeirsbilck, B., Berge, S.J., Hens, G., Schoenaers, J., Vander Poorten, V., Roosenboom, J., Verdonck, A., Devriendt, K., Roeleveldt, N., Jhangiani, S.N., Vissers, L.E., Lupski, J.R., de Ligt, J., Von den Hoff, J.W., Pfundt, R., Brunner, H.G., Zhou, H., Dixon, J., Mangold, E., van Bokhoven, H., Dixon, M.J., Kleefstra, T., Hoischen, A., Carels, C.E., Ockeloen, C.W., Khandelwal, K.D., Dreesen, K., Ludwig, K.U., Sullivan, R., Rooij, I.A van, Thonissen, M., Swinnen, S., Phan, M., Conte, F, Ishorst, N., Gilissen, C., Roa Fuentes, L., van de Vorst, M., Henkes, A., Steehouwer, M., van Beusekom, E., Bloemen, M., Vankeirsbilck, B., Berge, S.J., Hens, G., Schoenaers, J., Vander Poorten, V., Roosenboom, J., Verdonck, A., Devriendt, K., Roeleveldt, N., Jhangiani, S.N., Vissers, L.E., Lupski, J.R., de Ligt, J., Von den Hoff, J.W., Pfundt, R., Brunner, H.G., Zhou, H., Dixon, J., Mangold, E., van Bokhoven, H., Dixon, M.J., Kleefstra, T., Hoischen, A., and Carels, C.E.

Abstract

Item does not contain fulltext

Published
2016

7. Variability in dentofacial phenotypes in four families with WNT10A mutations

Author

Vink, C.P., Ockeloen, C.W., Ten Kate, S., Koolen, D.A., Ploos van Amstel, J.K., Kuijpers-Jagtman, A.M., Heumen, C.C.M. van, Kleefstra, T., Carels, C.E., Vink, C.P., Ockeloen, C.W., Ten Kate, S., Koolen, D.A., Ploos van Amstel, J.K., Kuijpers-Jagtman, A.M., Heumen, C.C.M. van, Kleefstra, T., and Carels, C.E.

Abstract

Item does not contain fulltext, This article describes the inter- and intra-familial phenotypic variability in four families with WNT10A mutations. Clinical characteristics of the patients range from mild to severe isolated tooth agenesis, over mild symptoms of ectodermal dysplasia, to more severe syndromic forms like odonto-onycho-dermal dysplasia (OODD) and Schopf-Schulz-Passarge syndrome (SSPS). Recurrent WNT10A mutations were identified in all affected family members and the associated symptoms are presented with emphasis on the dentofacial phenotypes obtained with inter alia three-dimensional facial stereophotogrammetry. A comprehensive overview of the literature regarding WNT10A mutations, associated conditions and developmental defects is presented. We conclude that OODD and SSPS should be considered as variable expressions of the same WNT10A genotype. In all affected individuals, a dished-in facial appearance was observed which might be helpful in the clinical setting as a clue to the underlying genetic etiology.

Published
2014

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