Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid
Open accessAbstract
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.
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The skeletal phenotype in POR deficiency probably results from diminished activity of CYP26B1, a POR-dependent enzyme that degrades retinoic acid.
“The skeletal phenotype probably results from diminished activity of CYP26B1, a POR-dependent enzyme that degrades retinoic acid (74).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [74]
The ABS skeletal phenotype in patients with POR deficiency probably results from diminished activity of CYP26B1, the POR-dependent microsomal enzyme that degrades retinoic acid.
“The ABS skeletal phenotype in patients with POR deficiency probably results from diminished activity of CYP26B1, the POR-dependent microsomal enzyme that degrades retinoic acid [ 63 ].”
From Steroidogenic electron-transfer factors and their diseases (2021) · cites this paper as [63]
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- Authors
- Laue, K., Pogoda, H.-M., Daniel, P. B., van Haeringen, A., Alanay, Y., von Ameln, S., Rachwalski, M., Morgan, T., Gray, M. J., Breuning, M. H., Sawyer, G. M., Sutherland-Smith, A. J., Nikkels, P. G., Kubisch, C., Bloch, W., Wollnik, B., Hammerschmidt, M., & Robertson, S. P.
- Affiliations
- University of Cologne (DE)
- University of Otago (NZ)
- Hacettepe University (TR)
- Leiden University Medical Center (NL)
- Massey University (NZ)
- University Medical Center Utrecht (NL)
- German Sport University Cologne (DE)
- Corresponding author
- Hammerschmidt, Matthias
- Robertson, Stephen P.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 89
- Issue
- 5
- Pages
- 595-606
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3213388
- OpenAlex
- W2090576305
- Cited by
- 188
- References
- 50
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 9 · 2023: 18 · 2022: 11 · 2021: 13 · 2020: 11 · 2019: 19 · 2018: 16 · 2017: 7 · 2016: 13 · 2015: 11 · 2014: 14 · 2013: 14 · 2012: 8
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Hacettepe University Institutional Repository (hacettepe.edu.tr) (submittedVersion, other-oa)
- GRO (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Keywords
- craniosynostosis, retinoic acid, CYP26B1, skeletal abnormalities, cranial sutures, osteogenic differentiation, chondrogenesis, zebrafish, mouse embryo, human mutations, craniofacial development
- MeSH terms
- Retinoic Acid 4-Hydroxylase, Animals, Cell Differentiation, Cranial Sutures, Craniosynostoses, Cytochrome P-450 Enzyme System, Disease Models, Animal, Female, Fetal Death, Humans, Osteoblasts, Osteogenesis, Polymorphism, Genetic, Pregnancy, Tretinoin, Zebrafish, Sequence Homology, Amino Acid, Gene Expression Regulation, Developmental, Zebrafish Proteins, Growth and Development, Mice, Cytochrome P-450 Enzyme Inhibitors
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