A Novel Gain-of-Function Mutation in BMPR2 in a Patient with Variant Fibrodysplasia Ossificans Progressiva
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Heterotopic ossification (HO), a pathological process in which bone forms in soft tissues is rare and debilitating without effective treatment. Gain-of-function mutations in ACVR1 cause fibrodysplasia ossificans progressiva (FOP). Here we report a novel, ultrarare gain of function mutation in BMPR2 (c.1126G > A, p.E376K) that causes a systemic HO simulating FOP. The pathological features associated with BMPR2 E376K appear reminiscent of classic FOP, yet manifest a number of distinct hallmarks, including lack of stereotypic malformation of the big toes. BMPR2 E376K appears to function as a neomorph, displaying an exaggerated response to Activin A stimulation by selectively interacting with ACVR1. These findings are consistent with the central role of Activin A mediated ACVR1 signaling in FOP. Taken together, our data illustrates the complex molecular features underlying the pathophysiology of HO and highlight the importance of BMPR2 as a nexus for ACVR1 and Activin A interaction. Moreover, our findings provide a theoretical framework for developing novel therapeutic options for HO.
