FLMNB causes progressive skeletal fusions via TGF-Beta/BMP signaling modulation

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 DESCRIPTION (provided by applicant): The development of both the axial and appendicular skeleton is a tightly regulated program leading to a highly sculpted organism. It is dependent on the interplay between multiple molecular pathways and differing mesenchymal derived structures as well as the overlying epithelium. The study of skeletal dysplasias, which affect 1 out of every 1,250 pregnancies, has given us the opportunity to dissect the molecular and genetic mechanisms that govern this highly complex process. Spondylocarpotarsal synostosis (SCT) is a rare disorder characterized by vertebral, carpal and tarsal bone fusions. This disorder results from homozygosity for nonsense mutations in Filamin B (FLNB). This gene encodes a protein that acts as a scaffold between the actin cytoskeleton network and molecular signaling cascades from the membrane to the cytoskeleton. I hypothesize that in skeletal tissues FLNB functions as an adaptor in TGFβ/BMP signaling. I also hypothesize that loss of FLNB influences the cell fate of tissues surrounding cartilage and bone promoting the development of fusions. Using both affected individuals as well as a mouse model; we are studying this disorder in order to gain a better understanding of the molecular function of FLNB and its role in endochondral skeletal formation while focusing on vertebral development. In addition, there are patients that phenocopy the SCT phenotype but do not harbor FLNB mutations. By discovering the underlying genetic cause of this cohort, we will identify more genes involved in vertebral development and maintenance. The central aim of this project is to use human phenotypes and mouse models of disease to elucidate the molecular mechanisms that participate in vertebral development and maintenance.