A rare bone disease gene found: SCUBE3 is required for proper bone formation
SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling
Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins. These SCUBE proteins appear to be multi-functional depending on their subcellular distribution and localization. These SCUBEs is not only secreted but also tethered on the cell surface as peripheral membrane proteins. When SCUBE proteins are tethered on the cell surface they form a complex with various growth factor receptors to act as a co-receptor in augmenting these growth factor signal activities including bone morphogenetic protein (BMP), sonic hedgehog (SHH), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) during physiological and pathological processes.
In this study, we reported that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We showed that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into lipid raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors.
Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identified a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.