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Am J Hum Genet ; 108(1): 115-133, 2021 01 07.
Article in English | MEDLINE | ID: mdl-33308444

ABSTRACT

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report 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 show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into 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 identify 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.


Subject(s)
Bone and Bones/metabolism , Calcium-Binding Proteins/metabolism , Developmental Disabilities/metabolism , Osteogenesis/physiology , Signal Transduction/physiology , Animals , Bone Morphogenetic Protein 2/metabolism , Bone Morphogenetic Protein 4/metabolism , Bone Morphogenetic Proteins/metabolism , Cell Line , Cell Line, Tumor , Female , Gene Expression Regulation, Developmental/physiology , HEK293 Cells , Hep G2 Cells , Humans , Intercellular Signaling Peptides and Proteins/metabolism , MCF-7 Cells , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL
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