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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. Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.


Yuh-Charn Lin, Marcello Niceta, Valentina Muto, Barbara Vona, Alistair T Pagnamenta, Reza Maroofian, Christian Beetz, Hermine van Duyvenvoorde, Maria Lisa Dentici, Peter Lauffer, Sadeq Vallian, Andrea Ciolfi, Simone Pizzi, Peter Bauer, Nana-Maria Grüning, Emanuele Bellacchio, Andrea Del Fattore, Stefania Petrini, Ranad Shaheen, Dov Tiosano, Rana Halloun, Ben Pode-Shakked, Hatice Mutlu Albayrak, Emregül Işık, Jan M Wit, Marcus Dittrich, Bruna L Freire, Debora R Bertola, Alexander A L Jorge, Ortal Barel, Ataf H Sabir, Amal M J Al Tenaiji, Sulaima M Taji, Nouriya Al-Sannaa, Hind Al-Abdulwahed, Maria Cristina Digilio, Melita Irving, Yair Anikster, Gandham S L Bhavani, Katta M Girisha, Genomics England Research Consortium, Thomas Haaf, Jenny C Taylor, Bruno Dallapiccola, Fowzan S Alkuraya, Ruey-Bing Yang, Marco Tartaglia. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling. American journal of human genetics. 2021 Jan 07;108(1):115-133

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PMID: 33308444

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