TY - JOUR
T1 - SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling
AU - Genomics England Research Consortium
AU - Lin, Yuh Charn
AU - Niceta, Marcello
AU - Muto, Valentina
AU - Vona, Barbara
AU - Pagnamenta, Alistair T.
AU - Maroofian, Reza
AU - Beetz, Christian
AU - van Duyvenvoorde, Hermine
AU - Dentici, Maria Lisa
AU - Lauffer, Peter
AU - Vallian, Sadeq
AU - Ciolfi, Andrea
AU - Pizzi, Simone
AU - Bauer, Peter
AU - Grüning, Nana Maria
AU - Bellacchio, Emanuele
AU - Del Fattore, Andrea
AU - Petrini, Stefania
AU - Shaheen, Ranad
AU - Tiosano, Dov
AU - Halloun, Rana
AU - Pode-Shakked, Ben
AU - Albayrak, Hatice Mutlu
AU - Işık, Emregül
AU - Wit, Jan M.
AU - Dittrich, Marcus
AU - Freire, Bruna L.
AU - Bertola, Debora R.
AU - Jorge, Alexander A.L.
AU - Barel, Ortal
AU - Sabir, Ataf H.
AU - Al Tenaiji, Amal M.J.
AU - Taji, Sulaima M.
AU - Al-Sannaa, Nouriya
AU - Al-Abdulwahed, Hind
AU - Digilio, Maria Cristina
AU - Irving, Melita
AU - Anikster, Yair
AU - Bhavani, Gandham S.L.
AU - Girisha, Katta M.
AU - Haaf, Thomas
AU - Taylor, Jenny C.
AU - Dallapiccola, Bruno
AU - Alkuraya, Fowzan S.
AU - Yang, Ruey Bing
AU - Tartaglia, Marco
N1 - Funding Information:
The authors wish to thank the participating families and Drs. R.A.J. Nievelstein (University Medical Center Utrecht) and D. Barbuti (Ospedale Pediatrico Bambino Gesù) for radiological advice. The authors would also thank Prof. Kassim Javaid and other members of musculoskeletal GeCIP (Genomics England). This research used data and findings generated by the 100,000 Genomes Project. This work was supported by grants from: Fondazione Bambino Gesù (Vite Coraggiose to M.T.) and Italian Ministry of Health ( CCR-2017-23669081 to M.T., Ricerca Corrente 2019 to M.N., and Ricerca Corrente 2019 and 2020 to M.L.D.), Academia Sinica and Ministry of Science and Technology of Taiwan ( 109-3111-Y-001-001 , 109-2320-B-001-012-MY3 , 107-3111-Y-001-048 , 107-0210-01-19-01 , 107-2320-B-001-015-MY3 , 106-2320-B-001-017-MY3 , 106-0210-01-15-02 to R.-B.Y. and 107-2321-B-001-036-MY3 to Y.-C.L.), São Paulo Research Foundation ( FAPESP 2013/03236-5 to A.A.L.J. and 2018/10893-6 to B.L.F.), University of Tübingen Intramural Funding ( fortüne 2545-1-0 to B.V.), Ministry of Science, Research and Art Baden-Württemberg (to B.V.), and Department of Science and Technology, Government of India ( SB/SO/HS/005/2014 to K.M.G.). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The 100,000 Genomes Project is managed by Genomics England Limited and uses data provided by patients and collected by the National Health Service as part of their care and support. See supplemental information for consortium details. Additional support was from the Wellcome Trust ( 203141/Z/16/Z ) and the NIHR Biomedical Research Centre Oxford (to A.T.P. and J.C.T.).
Publisher Copyright:
© 2020 American Society of Human Genetics
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2020.11.015
DO - 10.1016/j.ajhg.2020.11.015
M3 - Article
AN - SCOPUS:85098151529
SN - 0002-9297
VL - 108
SP - 115
EP - 133
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -