Dr. Yang, Ruey-Bing (Ray)'s publons link picture

Dr. Yang, Ruey-Bing (Ray)

Research Fellow
  • (02) 2789-9063 (Lab) (Room No: N427)
  • (02) 2652-3943
  • (02) 2785-8847 (Fax)

Specialty:

Signal transduction

Receptor biology

Vascular biology


Education and Positions:
  • Ph.D., University of Texas Southwestern Medical Center at Dallas

    Postdoctoral Fellow, Genentech, Inc.


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SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

Dr. Yang, Ruey-Bing (Ray)
American Journal of Human Genetics, Dec 11, 2020

Summary

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.