Universität zu Köln

Laue, Kathrin, Pogoda, Hans-Martin, Daniel, Philip B., van Haeringen, Arie, Alanay, Yasemin ORCID: 0000-0003-0683-9731, von Ameln, Simon ORCID: 0000-0002-2242-3165, Rachwalski, Martin, Morgan, Tim, Gray, Mary J., Breuning, Martijn H., Sawyer, Gregory M., Sutherland-Smith, Andrew J., Nikkels, Peter G., Kubisch, Christian ORCID: 0000-0003-4220-0978, Bloch, Wilhelm, Wollnik, Bernd, Hammerschmidt, Matthias and Robertson, Stephen P. (2011). Craniosynostosis and Multiple Skeletal Anomalies in Humans and Zebrafish Result from a Defect in the Localized Degradation of Retinoic Acid. Am. J. Hum. Genet., 89 (5). S. 595 - 607. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Laue, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pogoda, Hans-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Daniel, Philip B. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Haeringen, Arie UNSPECIFIED UNSPECIFIED UNSPECIFIED Alanay, Yasemin UNSPECIFIED orcid.org/0000-0003-0683-9731 UNSPECIFIED von Ameln, Simon UNSPECIFIED orcid.org/0000-0002-2242-3165 UNSPECIFIED Rachwalski, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Morgan, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Gray, Mary J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Breuning, Martijn H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sawyer, Gregory M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sutherland-Smith, Andrew J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikkels, Peter G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammerschmidt, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Robertson, Stephen P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-485398
DOI:	10.1016/j.ajhg.2011.09.015
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	89
Number:	5
Page Range:	S. 595 - 607
Date:	2011
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SITE-DIRECTED MUTAGENESIS; CYTOCHROME-P450 OXIDOREDUCTASE; METABOLIZING ENZYME; CRYSTAL-STRUCTURES; MOUSE; GROWTH; CYP26B1; LIMB; OSTEOGENESIS; ORGANOGENESIS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48539