Change-of-function fibroblast growth factor receptor 3 mutations causing skeletal dysplasias

Fibroblast growth factor receptor 3 (FGFR3) is a membrane protein that plays a critical role as a negative regulator in the growth and development of the skeletal system. Mutations in FGFR3 cause a range of skeletal dysplasias. The G380R mutation in FGFR3 causes achondroplasia (ACH), the most common form of human short-limbed dwarfism, whereas the A391E mutation in FGFR3 causes Crouzon syndrome, a craniosynostosis characterized by premature fusion of sutures between the cranial bones, with acanthosis nigricans. Both mutations are considered "gain-of-function" and occur close to each other within the simple FGFR3 helix that spans the membrane. Yet, the two pathological phenotypes of ACH and Crouzon syndrome are distinctly different. Here, we show that FGFR3 engages in biased signaling. We further show that the G380R and A391E mutations do not simply amplify signaling but differentially reshape the FGFR3 signaling patterns. The data provide an explanation of the distinctly different phenotypes due to the two mutations and lead us to propose that the mutations are "change-of-function."