SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling
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 o...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2020
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| _version_ | 1797068236656738304 |
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| author | Lin, Y-C Niceta, M Muto, V Vona, B Pagnamenta, AT Maroofian, R Beetz, C van Duyvenvoorde, H Dentici, ML Lauffer, P Vallian, S Ciolfi, A Pizzi, S Bauer, P Grüning, N-M Bellacchio, E Del Fattore, A Petrini, S Shaheen, R Tiosano, D Halloun, R Pode-Shakked, B Albayrak, HM Işık, E Wit, JM Dittrich, M Freire, BL Bertola, DR Jorge, AAL Barel, O Sabir, AH Al Tenaiji, AMJ Taji, SM Al-Sannaa, N Al-Abdulwahed, H Digilio, MC Irving, M Anikster, Y Bhavani, GSL Girisha, KM Haaf, T Taylor, JC Dallapiccola, B Alkuraya, FS Yang, R-B Tartaglia, M |
| author2 | Genomics England Research Consortium |
| author_facet | Genomics England Research Consortium Lin, Y-C Niceta, M Muto, V Vona, B Pagnamenta, AT Maroofian, R Beetz, C van Duyvenvoorde, H Dentici, ML Lauffer, P Vallian, S Ciolfi, A Pizzi, S Bauer, P Grüning, N-M Bellacchio, E Del Fattore, A Petrini, S Shaheen, R Tiosano, D Halloun, R Pode-Shakked, B Albayrak, HM Işık, E Wit, JM Dittrich, M Freire, BL Bertola, DR Jorge, AAL Barel, O Sabir, AH Al Tenaiji, AMJ Taji, SM Al-Sannaa, N Al-Abdulwahed, H Digilio, MC Irving, M Anikster, Y Bhavani, GSL Girisha, KM Haaf, T Taylor, JC Dallapiccola, B Alkuraya, FS Yang, R-B Tartaglia, M |
| author_sort | Lin, Y-C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:07:49Z |
| format | Journal article |
| id | oxford-uuid:50c1a2ab-6630-4fa7-ae4d-495b44019a40 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:07:49Z |
| publishDate | 2020 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:50c1a2ab-6630-4fa7-ae4d-495b44019a402022-03-26T16:15:35ZSCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signalingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:50c1a2ab-6630-4fa7-ae4d-495b44019a40EnglishSymplectic ElementsCell Press2020Lin, Y-CNiceta, MMuto, VVona, BPagnamenta, ATMaroofian, RBeetz, Cvan Duyvenvoorde, HDentici, MLLauffer, PVallian, SCiolfi, APizzi, SBauer, PGrüning, N-MBellacchio, EDel Fattore, APetrini, SShaheen, RTiosano, DHalloun, RPode-Shakked, BAlbayrak, HMIşık, EWit, JMDittrich, MFreire, BLBertola, DRJorge, AALBarel, OSabir, AHAl Tenaiji, AMJTaji, SMAl-Sannaa, NAl-Abdulwahed, HDigilio, MCIrving, MAnikster, YBhavani, GSLGirisha, KMHaaf, TTaylor, JCDallapiccola, BAlkuraya, FSYang, R-BTartaglia, MGenomics England Research ConsortiumSignal 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. |
| spellingShingle | Lin, Y-C Niceta, M Muto, V Vona, B Pagnamenta, AT Maroofian, R Beetz, C van Duyvenvoorde, H Dentici, ML Lauffer, P Vallian, S Ciolfi, A Pizzi, S Bauer, P Grüning, N-M Bellacchio, E Del Fattore, A Petrini, S Shaheen, R Tiosano, D Halloun, R Pode-Shakked, B Albayrak, HM Işık, E Wit, JM Dittrich, M Freire, BL Bertola, DR Jorge, AAL Barel, O Sabir, AH Al Tenaiji, AMJ Taji, SM Al-Sannaa, N Al-Abdulwahed, H Digilio, MC Irving, M Anikster, Y Bhavani, GSL Girisha, KM Haaf, T Taylor, JC Dallapiccola, B Alkuraya, FS Yang, R-B Tartaglia, M SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title | SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title_full | SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title_fullStr | SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title_full_unstemmed | SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title_short | SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
| title_sort | scube3 loss of function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling |
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