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SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.
Lin, Yuh-Charn; Niceta, Marcello; Muto, Valentina; Vona, Barbara; Pagnamenta, Alistair T; Maroofian, Reza; Beetz, Christian; van Duyvenvoorde, Hermine; Dentici, Maria Lisa; Lauffer, Peter; Vallian, Sadeq; Ciolfi, Andrea; Pizzi, Simone; Bauer, Peter; Grüning, Nana-Maria; Bellacchio, Emanuele; Del Fattore, Andrea; Petrini, Stefania; Shaheen, Ranad; Tiosano, Dov; Halloun, Rana; Pode-Shakked, Ben; Albayrak, Hatice Mutlu; Isik, Emregül; Wit, Jan M; Dittrich, Marcus; Freire, Bruna L; Bertola, Debora R; Jorge, Alexander A L; Barel, Ortal; Sabir, Ataf H; Al Tenaiji, Amal M J; Taji, Sulaima M; Al-Sannaa, Nouriya; Al-Abdulwahed, Hind; Digilio, Maria Cristina; Irving, Melita; Anikster, Yair; Bhavani, Gandham S L; Girisha, Katta M; Haaf, Thomas; Taylor, Jenny C; Dallapiccola, Bruno; Alkuraya, Fowzan S; Yang, Ruey-Bing; Tartaglia, Marco.
Afiliação
  • Lin YC; Department of Physiology, School of Medicine, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan.
  • Niceta M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Muto V; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Vona B; Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Otolaryngology - Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.
  • Pagnamenta AT; NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
  • Maroofian R; Genetics and Molecular Cell Sciences Research Centre, St George's University of London, Cranmer Terrace, SW17 0RE London, UK.
  • Beetz C; Centogene AG, 18055 Rostock, Germany.
  • van Duyvenvoorde H; Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
  • Dentici ML; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Lauffer P; Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
  • Vallian S; Department of Cell and Molecular Biology & Microbiology, University of Isfahan, 8174673441 Isfahan, Iran.
  • Ciolfi A; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Pizzi S; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Bauer P; Centogene AG, 18055 Rostock, Germany.
  • Grüning NM; Centogene AG, 18055 Rostock, Germany.
  • Bellacchio E; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Del Fattore A; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Petrini S; Confocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
  • Shaheen R; 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.
  • Tiosano D; 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.
  • Halloun R; Pediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel.
  • Pode-Shakked B; 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.
  • Albayrak HM; Department of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.
  • Isik E; Department of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.
  • Wit JM; Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
  • Dittrich M; Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Institute of Bioinformatics, Julius Maximilians University, 97070 Würzburg, Germany.
  • Freire BL; Unidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.
  • Bertola DR; Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 05403000 Sao Paulo, Brazil.
  • Jorge AAL; Unidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.
  • Barel O; Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • Sabir AH; 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.
  • Al Tenaiji AMJ; Department of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.
  • Taji SM; Department of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.
  • Al-Sannaa N; Johns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.
  • Al-Abdulwahed H; Johns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.
  • Digilio MC; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Irving M; Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK.
  • Anikster Y; 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.
  • Bhavani GSL; Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
  • Girisha KM; Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
  • Haaf T; Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
  • Taylor JC; NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
  • Dallapiccola B; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia.
  • Yang RB; 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, Tai
  • Tartaglia M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
Am J Hum Genet ; 108(1): 115-133, 2021 01 07.
Article em En | MEDLINE | ID: mdl-33308444
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteogênese / Osso e Ossos / Proteínas de Ligação ao Cálcio / Transdução de Sinais / Deficiências do Desenvolvimento Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteogênese / Osso e Ossos / Proteínas de Ligação ao Cálcio / Transdução de Sinais / Deficiências do Desenvolvimento Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article