Background
Bent bone dysplasia syndrome (BBDS), a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2), is characterized by bowed long bones within the limbs. We previously showed that the FGFR2 mutations in BBDS enhance nuclear and nucleolar localization of the receptor; however, exactly how shifts in subcellular distribution of FGFR2 affect limb development remained unknown.
Conclusions
Our results indicate that the bent long bones in BBDS arise from disruptions in musculoskeletal integration and that increased nuclear and nucleolar localization of FGFR2 plays a mechanistic role in the disease phenotype. 248:233-246, 2019. © 2018 Wiley Periodicals, Inc.
Results
Targeted expression of the BBDS mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, a hallmark feature of the disease. Whole-mount analysis of the underlying skeleton revealed bent long bones with shortened bone collars and, in severe cases, dysmorphic epiphyses. Epiphyseal changes were also correlated with joint dislocations and contractures. Histological analysis revealed that bent long bones and joint defects were closely associated with irregularities in skeletal muscle patterning and tendon-to-bone attachment. The spectrum of limb phenotypes induced by the BBDS mutations were recapitulated by targeted expression of wild-type FGFR2 appended with nuclear and nucleolar localization signals. Conclusions: Our results indicate that the bent long bones in BBDS arise from disruptions in musculoskeletal integration and that increased nuclear and nucleolar localization of FGFR2 plays a mechanistic role in the disease phenotype. 248:233-246, 2019. © 2018 Wiley Periodicals, Inc.