2. Academic Validation
  3. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling

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

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: rbyang@ibms.sinica.edu.tw.
  • 30 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
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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