Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 1, Pages 115-133Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.11.015
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Funding
- Fondazione Bambino Gesu` (Vite Coraggiose)
- Italian Ministry of Health [CCR-2017-23669081]
- Academia Sinica
- Ministry of Science and Technology of Taiwan [109-3111-Y001-001, 109-2320-B-001-012-MY3, 107-3111-Y-001-048, 1070210-01-19-01, 107-2320-B-001-015-MY3, 106-2320-B-001-017MY3, 106-0210-01-15-02, 107-2321-B-001-036MY3]
- Sa~o Paulo Research Foundation [FAPESP 2013/03236-5, 2018/10893-6]
- University of Tubingen Intramural Funding [fortune 2545-1-0]
- Ministry of Science, Research and Art Baden-Wurttemberg
- Department of Science and Technology, Government of India [SB/SO/HS/005/2014]
- National Institute for Health Research
- NHS England
- Wellcome Trust [203141/Z/16/Z]
- NIHR Biomedical Research Centre Oxford
- National Health Service
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [18/10893-6] Funding Source: FAPESP
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Bi-allelic inactivating variants in SCUBE3 gene result in a previously unrecognized syndromic disorder characterized by growth retardation, skeletal abnormalities, distinctive craniofacial features, and dental anomalies. Functional studies demonstrate the involvement of SCUBE3 in modulating BMP signaling pathway to regulate growth, morphogenesis, bone, and teeth development. Knockout mice for SCUBE3 exhibit similar phenotypes, implicating the crucial role of SCUBE3 in these processes.
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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