SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

  • Am J Hum Genet. 2021 Jan 7;108(1):115-133. doi: 10.1016/j.ajhg.2020.11.015.
Yuh-Charn Lin  1 ,  Marcello Niceta  2 ,  Valentina Muto  2 ,  Barbara Vona  3 ,  Alistair T Pagnamenta  4 ,  Reza Maroofian  5 ,  Christian Beetz  6 ,  Hermine van Duyvenvoorde  7 ,  Maria Lisa Dentici  2 ,  Peter Lauffer  8 ,  Sadeq Vallian  9 ,  Andrea Ciolfi  2 ,  Simone Pizzi  2 ,  Peter Bauer  6 ,  Nana-Maria Grüning  6 ,  Emanuele Bellacchio  2 ,  Andrea Del Fattore  2 ,  Stefania Petrini  10 ,  Ranad Shaheen  11 ,  Dov Tiosano  12 ,  Rana Halloun  13 ,  Ben Pode-Shakked  14 ,  Hatice Mutlu Albayrak  15 ,  Emregül Işık  15 ,  Jan M Wit  16 ,  Marcus Dittrich  17 ,  Bruna L Freire  18 ,  Debora R Bertola  19 ,  Alexander A L Jorge  18 ,  Ortal Barel  20 ,  Ataf H Sabir  21 ,  Amal M J Al Tenaiji  22 ,  Sulaima M Taji  22 ,  Nouriya Al-Sannaa  23 ,  Hind Al-Abdulwahed  23 ,  Maria Cristina Digilio  2 ,  Melita Irving  24 ,  Yair Anikster  25 ,  Gandham S L Bhavani  26 ,  Katta M Girisha  26 ,  Genomics England Research Consortium ,  Thomas Haaf  27 ,  Jenny C Taylor  4 ,  Bruno Dallapiccola  2 ,  Fowzan S Alkuraya  28 ,  Ruey-Bing Yang  29 ,  Marco Tartaglia  30
Affiliations
  • 1. Department of Physiology, School of Medicine, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan.
  • 2. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 3. Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Otolaryngology - Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.
  • 4. NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
  • 5. Genetics and Molecular Cell Sciences Research Centre, St George's University of London, Cranmer Terrace, SW17 0RE London, UK.
  • 6. Centogene AG, 18055 Rostock, Germany.
  • 7. Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
  • 8. Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
  • 9. Department of Cell and Molecular Biology & Microbiology, University of Isfahan, 8174673441 Isfahan, Iran.
  • 10. Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
  • 11. Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, 34110 Doha, Qatar.
  • 12. Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, 352540 Haifa, Israel.
  • 13. Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel.
  • 14. Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.
  • 15. Department of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.
  • 16. Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
  • 17. Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Institute of Bioinformatics, Julius Maximilians University, 97070 Würzburg, Germany.
  • 18. Unidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.
  • 19. Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 05403000 Sao Paulo, Brazil.
  • 20. Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 21. Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK; Birmingham Women's and Children's NHS Foundation Trust, University of Birmingham, B4 6NH Birmingham, UK.
  • 22. Department of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.
  • 23. Johns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.
  • 24. Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK.
  • 25. Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 26. Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
  • 27. Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
  • 28. Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia.
  • 29. Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, 112304, Taipei, Taiwan. Electronic address: [email protected].
  • 30. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: [email protected].
PMID: 33308444 DOI: 10.1016/j.ajhg.2020.11.015
Abstract

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.

Keywords
BMP; BMP receptors; SCUBE; bone morphogenetic protein; genomic sequencing; intracellular signaling; mechanism of disease; morphogenesis; skeletal development.
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