Expression profiles of craniosynostosis-derived fibroblasts

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Craniosynostosis syndromes involve connective tissue disorders with abnormal bone development and premature suture fusion.
• These syndromes are often linked to mutations in Fibroblast Growth Factor (FGF) receptor genes.
• A hallmark cellular phenotype includes dysregulated extracellular matrix turnover.

Purpose of the Study:

• To investigate the gene expression profiles of fibroblasts from Apert and Crouzon craniosynostosis syndromes.
• To compare these profiles with wild-type fibroblasts and identify distinct molecular signatures.
• To explore the genetic basis underlying these distinct craniosynostosis phenotypes.

Main Methods:

• Primary periosteal fibroblasts were cultured from patients with Apert and Crouzon syndromes.
• Fibroblast DNA was analyzed for mutations in the FGFR2 gene.
• DNA microarrays were employed to assess gene expression profiles of 19,200 cDNAs.

Main Results:

• Specific mutations (P253R in Apert, G338R in Crouzon) were identified in FGFR2.
• Craniosynostosis fibroblasts exhibited significantly different gene expression profiles compared to wild-type fibroblasts (288 human ESTs, p<0.01).
• Two distinct clusters of expressed sequence tags (ESTs) differentiated Apert from Crouzon fibroblasts, involving genes in bone differentiation, cell cycle, apoptosis, and signaling.

Conclusions:

• The transcriptional program in craniosynostosis fibroblasts is demonstrably different from that of normal fibroblasts.
• Distinct gene expression patterns exist between Apert and Crouzon fibroblasts, suggesting different genetic etiologies.
• These findings highlight the utility of gene expression profiling in understanding craniosynostosis heterogeneity.