ArticleAmerican journal of human genetics2021
SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 65 citations in OpenAlex.
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Authors and funding
47 authors at 20 institutions in 13 countries.
Yuh-Charn LinDepartment of Physiology, School of Medicine, Taipei Medical University, 110301 Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, 115201 Taipei, Taiwan.
Marcello NicetaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Valentina MutoGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Barbara VonaInstitute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Otolaryngology - Head and Neck Surgery, Eberhard Karls University, 72076 Tübingen, Germany.
Alistair T PagnamentaNIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Reza MaroofianGenetics and Molecular Cell Sciences Research Centre, St George's University of London, Cranmer Terrace, SW17 0RE London, UK.
Christian BeetzCentogene AG, 18055 Rostock, Germany.
Hermine van DuyvenvoordeDepartment of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Maria Lisa DenticiGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Peter LaufferDepartment of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, 1105 AZ Amsterdam, the Netherlands.
Sadeq VallianDepartment of Cell and Molecular Biology & Microbiology, University of Isfahan, 8174673441 Isfahan, Iran.
Andrea CiolfiGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Simone PizziGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Peter BauerCentogene AG, 18055 Rostock, Germany.
Nana-Maria GrüningCentogene AG, 18055 Rostock, Germany.
Emanuele BellacchioGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Andrea Del FattoreGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Stefania PetriniConfocal Microscopy Core Facility, Research Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Ranad ShaheenDepartment of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia; Qatar Biomedical Research Institute, Hamad Bin Khalifa University, 34110 Doha, Qatar.
Dov TiosanoPediatric 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.
Rana HallounPediatric Endocrinology Unit, Ruth Rappaport Children's Hospital, Rambam Healthcare Campus, 352540 Haifa, Israel.
Ben Pode-ShakkedEdmond 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.
Hatice Mutlu AlbayrakDepartment of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.
Emregül IşıkDepartment of Pediatric Endocrinology, Gaziantep Cengiz Gökcek Maternity & Children's Hospital, 27010 Gaziantep, Turkey.
Jan M WitDepartment of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
Marcus DittrichInstitute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Institute of Bioinformatics, Julius Maximilians University, 97070 Würzburg, Germany.
Bruna L FreireUnidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.
Debora R BertolaUnidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 05403000 Sao Paulo, Brazil.
Alexander A L JorgeUnidade de Endocrinologia Genética, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo, 01246903 Sao Paulo, Brazil.
Ortal BarelSheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Wohl Institute for Translational Medicine, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
Ataf H SabirDepartment 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.
Amal M J Al TenaijiDepartment of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.
Sulaima M TajiDepartment of Paediatrics, Sheikh Khalifa Medical City, 51900 Abu Dhabi, United Arab Emirates.
Nouriya Al-SannaaJohns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.
Hind Al-AbdulwahedJohns Hopkins Aramco Healthcare, 34465 Dhahran, Saudi Arabia.
Maria Cristina DigilioGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Melita IrvingDepartment of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, SE1 9RT London, UK.
Yair AniksterEdmond 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.
Gandham S L BhavaniDepartment of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
Katta M GirishaDepartment of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India.
Genomics England Research Consortium
Thomas HaafInstitute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
Jenny C TaylorNIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
Bruno DallapiccolaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
Fowzan S AlkurayaDepartment of Genetics, King Faisal Specialist Hospital and Research Center, 11211 Riyadh, Saudi Arabia.
Ruey-Bing YangInstitute 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.
Marco TartagliaGenetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: marco.tartaglia@opbg.net.
Istituti di Ricovero e Cura a Carattere Scientifico · ITBambino Gesù Children's Hospital · ITCentogene (Germany) · DEHospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo · BRGaziantep Children's Hospital · TRGuy's and St Thomas' NHS Foundation Trust · GBInstitute of Biomedical Sciences, Academia Sinica · TWKing Faisal Specialist Hospital & Research Centre · SALeiden University Medical Center · NLRambam Health Care Campus · ILSaudi Aramco Medical Services Organization · SAShaikh Khalifa Medical City · AEUniversity of Oxford · GBEdmond and Lily Safra Children's Hospital · ILEmma Kinderziekenhuis · NLKasturba Medical College, Manipal · INManipal Academy of Higher Education · INSheba Medical Center · ILSt George's, University of London · GBTel Aviv University · IL
Funding
Wellcome TrustWellcome Trust 203141/Z/16/Z
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
Indexed as
AnimalsBone and BonesBone Morphogenetic Protein 2Bone Morphogenetic Protein 4Bone Morphogenetic ProteinsCalcium-Binding ProteinsCell LineCell Line, TumorDevelopmental DisabilitiesFemaleGene Expression Regulation, DevelopmentalHEK293 CellsHep G2 CellsHumansIntercellular Signaling Peptides and ProteinsMaleBone Morphogenetic Protein 2Bone Morphogenetic Protein 4Bone Morphogenetic ProteinsCalcium-Binding ProteinsIntercellular Signaling Peptides and ProteinsSCUBE3 protein, humanBMPBMP receptorsbone morphogenetic proteingenomic sequencingintracellular signalingmechanism of diseasemorphogenesisSCUBEskeletal development
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