FGFR1 frameshift mutation mediates the dysfunction of mesenchymal stem cells in craniofacial microsomia.

Craniofacial microsomia represents a congenital craniofacial anomaly characterized by a complex etiology, the precise genetic determinants of CFM have remained largely elusive. Comprehensive exome sequencing analysis performed on a cohort of CFM patients has identified a specific pathogenic frameshift mutation (c.225dupA, p. I76fs) located within the Fibroblast Growth Factor Receptor 1 gene. Extensive functional characterization utilizing human umbilical cord-derived mesenchymal stem cells demonstrated that either the presence of this FGFR1 mutation or the targeted knockdown of FGFR1 significantly attenuated the endogenous expression of the receptor. This genetic perturbation was associated with a marked impairment of osteogenic differentiation potential, a substantial reduction in cellular proliferative and migratory capacities, and an exacerbated apoptotic response. From a mechanistic perspective, the disruption of FGFR1 function exerted a suppressive effect on pivotal signaling cascades essential for skeletal development, including the P38/ERK, Wnt/β-catenin, BMP2/SMAD4, and PI3K/AKT transduction axes. Furthermore, the integrity of critical molecular interactions between FGFR1 and structural co-factors, specifically vimentin, COL1A1, and FGF1, was compromised, resulting in a concomitant downregulation of their protein abundance. Collectively, these findings elucidate that the FGFR1 frameshift mutation is a significant contributor to the pathogenesis of CFM, principally by obstructing MSC-mediated osteogenesis through the dual disruption of essential signal transduction pathways and vital protein-protein interaction networks.