SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling
| Autor: | Lin, Y.C., Niceta, M., Muto, V., Vona, B., Pagnamenta, A.T., Maroofian, R., Beetz, C., Duyvenvoorde, H. van, Dentici, M.L., Lauffer, P., Vallian, S., Ciolfi, A., Pizzi, S., Bauer, P., Gruning, N.M., Bellacchio, E., Fattore, A. del, Petrini, S., Shaheen, R., Tiosano, D., Halloun, R., Pode-Shakked ben, Albayrak, H.M., Isik, E., Wit, J.M., Dittrich, M., Freire, B.L., Bertola, D.R., Jorge, A.A.L., Barel, O., Sabir, A.H., Tenaiji, A.M.J. al, Taji, S.M., Al-Sannaa, N., Al-Abdulwahed, H., Digilio, M.C., Irving, M., Anikster, Y., Bhavani, G.S.L., Girisha, K.M., Haaf, T., Taylor, J.C., Dallapiccola, B., Alkuraya, F.S., Yang, R.B., Tartaglia, M., Genomics England Res Consortium |
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| Přispěvatelé: | Consortium, Genomics England Research, Graduate School, Paediatric Endocrinology, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine SCUBE Developmental Disabilities mechanism of disease Morphogenesis Bone Morphogenetic Protein 2 morphogenesis Bone Morphogenetic Protein 4 Biology Bone morphogenetic protein Bone morphogenetic protein 2 Article Bone and Bones Cell Line Mice 03 medical and health sciences 0302 clinical medicine Osteogenesis Cell Line Tumor bone morphogenetic protein Genetics Animals Humans BMP Receptor Genetics (clinical) Loss function Mice Inbred C3H Calcium-Binding Proteins intracellular signaling Gene Expression Regulation Developmental skeletal development Hep G2 Cells Chondrogenesis Phenotype Endochondral bone growth Cell biology Mice Inbred C57BL HEK293 Cells 030104 developmental biology Bone Morphogenetic Proteins genomic sequencing MCF-7 Cells Intercellular Signaling Peptides and Proteins Female BMP receptors 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | American Journal of Human Genetics, 108(1), 115-133. CELL PRESS American journal of human genetics, 108(1), 115-133. Cell Press Am J Hum Genet |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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