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[From gene to disease; craniosynostosis syndromes due to FGFR2-mutation]
C M A van Ravenswaaij-Arts1, A M W van den Ouweland, A J M Hoogeboom
1Universitair Medisch Centrum St Radboud, afd. Antropogenetica 417, Postbus 9101, 6500 HB Nijmegen. c.vanravenswaay@antrg.azn.nl
Abstract:
One of the genes involved in craniosynostosis syndromes is the fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor gene. Upon ligand binding the FGFR2 receptors dimerise, and this is followed by activation of the intracellular tyrosine kinase domains. This initiates a cascade of signals that influence cell division and differentiation. FGFR2 mutations have been found in the Apert, Crouzon and Pfeiffer craniosynostosis syndromes. Most mutations are gain of function mutations, inducing ligand-independent receptor activation or altered ligand binding. With the exception of Apert syndrome, there is no clear genotype-phenotype correlation. Many different mutations have been found in Pfeiffer and Crouzon syndrome, but all of the mutations occur in the same extracellular region of the receptor. Identical mutations have been found in Pfeiffer and Crouzon syndrome. So within one family, both Crouzon and Pfeiffer syndrome may occur. Mutations in other FGFR-genes have also been found in craniosynostosis syndromes.
Insights
Fibroblast growth factor receptor 2 (FGFR2) gene mutations are linked to craniosynostosis syndromes like Apert, Crouzon, and Pfeiffer. Most mutations cause gain-of-function, leading to ligand-independent receptor activation.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Context:
- Craniosynostosis syndromes are congenital disorders characterized by the premature fusion of skull sutures.
- The fibroblast growth factor receptor 2 (FGFR2) gene, a tyrosine kinase receptor, plays a crucial role in skeletal development.
- Mutations in FGFR2 are implicated in several craniosynostosis syndromes, including Apert, Crouzon, and Pfeiffer syndromes.
Purpose:
- To investigate the role of fibroblast growth factor receptor 2 (FGFR2) gene mutations in craniosynostosis syndromes.
- To understand the molecular mechanisms underlying FGFR2-mediated signaling in craniofacial development.
- To explore the genotype-phenotype correlations in patients with FGFR2 mutations.
Summary:
- FGFR2 is a tyrosine kinase receptor involved in cell division and differentiation.
- Mutations in FGFR2, predominantly gain-of-function, lead to ligand-independent receptor activation or altered ligand binding.
- While Apert syndrome shows some genotype-phenotype correlation, Crouzon and Pfeiffer syndromes exhibit overlapping mutations in the same extracellular receptor region, sometimes occurring within the same family.
Impact:
- Elucidates the genetic basis of craniosynostosis syndromes, particularly those associated with FGFR2.
- Provides insights into the molecular pathogenesis of craniofacial abnormalities.
- Highlights the complexity of genotype-phenotype relationships in genetic disorders and suggests potential for shared genetic factors across different syndromes.