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

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Lin, Yuh-Charn ^{[1, 2]} ; Niceta, Marcello ^[3] ; Muto, Valentina ^[3] ; Vona, Barbara ^{[4, 5]} ; Pagnamenta, Alistair T. ^[6] ; Maroofian, Reza ^[7] ; Beetz, Christian ^[8] ; van Duyvenvoorde, Hermine ^[9] ; Dentici, Maria Lisa ^[3] ; Lauffer, Peter ^[10] ; Vallian, Sadeq ^[11] ; Ciolfi, Andrea ^[3] ; Pizzi, Simone ^[3] ; Bauer, Peter ^[8] ; Gruening, Nana-Maria ^[8] ; Bellacchio, Emanuele ^[3] ; Del Fattore, Andrea ^[3] ; Petrini, Stefania ^[12] ; Shaheen, Ranad ^{[13, 14]} ; Tiosano, Dov ^{[15, 16]} ; Halloun, Rana ^[15] ; Pode-Shakked, Ben ; Albayrak, Hatice Mutlu ^[17] ; Isik, Emreguel ^[17] ; Wit, Jan M. ^[18] ; Dittrich, Marcus ^{[4, 19]} ; Freire, Bruna L. ^[20] ; Bertola, Debora R. ^[21] ; Jorge, Alexander A. L. ^[20] ; Barel, Ortal ^{[22, 23]} ; Sabir, Ataf H. ^{[24, 25]} ; Al Tenaiji, Amal M. J. ^[26] ; Taji, Sulaima M. ^[26] ; Al-Sannaa, Nouriya ^[27] ; Al-Abdulwahed, Hind ^[27] ; Digilio, Maria Cristina ^[3] ; Irving, Melita ^[24] ; Anikster, Yair ^{[28, 29, 22]} ; Bhavani, Gandham S. L. ^[30] ; Girisha, Katta M. ^[30] ; Haaf, Thomas ^[4] ; Taylor, Jenny C. ^[6] ; Dallapiccola, Bruno ^[3] ; Alkuraya, Fowzan S. ^[13] ; Yang, Ruey-Bing ^{[2, 31, 32]} ; Tartaglia, Marco ^[3] ; Consortium, Genomics England Res

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^[1] Taipei Med Univ, Dept Physiol, Sch Med, Taipei 110301 - Taiwan

^[2] Acad Sinica, Inst Biomed Sci, Taipei 115201 - Taiwan

^[3] Osped Pediat Bambino Gesu, IRCCS, Genet & Rare Dis Res Div, I-00146 Rome - Italy

^[4] Julius Maximilians Univ, Inst Human Genet, D-97074 Wurzburg - Germany

^[5] Eberhard Karls Univ Tubingen, Dept Otolaryngol Head & Neck Surg, D-72076 Tubingen - Germany

^[6] Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Ctr Human Genet, Oxford OX3 7BN - England

^[7] St Georges Univ London, Genet & Mol Cell Sci Res Ctr, Cranmer Terrace, London SW17 0RE - England

^[8] Centogene AG, D-18055 Rostock - Germany

^[9] Leiden Univ, Dept Clin Genet, Med Ctr, NL-2300 RC Leiden - Netherlands

^[10] Univ Amsterdam, Emma Childrens Hosp, Dept Paediat Endocrinol, Med Ctr, NL-1105 AZ Amsterdam - Netherlands

^[11] Univ Isfahan, Dept Cell & Mol Biol & Microbiol, Esfahan 8174673441 - Iran

^[12] IRCCS Osped Pediat Bambino Gesu, Res Labs, Confocal Microscopy Core Facil, I-00146 Rome - Italy

^[13] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211 - Saudi Arabia

^[14] Hamad Bin Khalifa Univ, Qatar Biomed Res Inst, Doha 34110 - Qatar

^[15] Ruth Rappaport Childrens Hosp, Pediat Endocrinol Unit, Rambam Healthcare Campus, IL-352540 Haifa - Israel

^[16] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, IL-352540 Haifa - Israel

^[17] Gaziantep Cengiz Gokcek Matern & Childrens Hosp, Dept Pediat Endocrinol, TR-27010 Gaziantep - Turkey

^[18] Leiden Univ, Dept Pediat, Med Ctr, NL-2333 ZA Leiden - Netherlands

^[19] Julius Maximilians Univ, Inst Bioinformat, D-97070 Wurzburg - Germany

^[20] Univ Sao Paulo, Unidade Endocrinol Genet, Hosp Clin, Fac Med, BR-01246903 Sao Paulo - Brazil

^[21] Univ Sao Paulo, Unidade Genet, Inst Crianca, Hosp Clin, Fac Med, BR-05403000 Sao Paulo - Brazil

^[22] Sheba Med Ctr, Wohl Inst Translat Med, IL-52621 Tel Hashomer - Israel

^[23] Sheba Med Ctr, Sheba Canc Res Ctr, IL-52621 Tel Hashomer - Israel

^[24] Guys & St Thomas NHS Fdn Trust, Dept Clin Genet, London SE1 9RT - England

^[25] Univ Birmingham, Birmingham Womens & Childrens NHS Fdn Trust, Birmingham B4 6NH, W Midlands - England

^[26] Sheikh Khalifa Med City, Dept Paediat, Abu Dhabi 51900 - U Arab Emirates

^[27] Johns Hopkins Aramco Healthcare, Dhahran 34465 - Saudi Arabia

^[28] Ben Pode-Shakked, Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, IL-52621 Tel Hashomer - Israel

^[29] Ben Pode-Shakked, Tel Aviv Univ, Sackler Fac Med, IL-6997801 Tel Aviv - Israel

^[30] Manipal Acad Higher Educ, Kasturba Med Coll, Dept Med Genet, Manipal 576104 - India

^[31] Taipei Med Univ, Coll Pharm, PhD Program Drug Discovery & Dev Ind, Taipei 110301 - Taiwan

^[32] Natl Yang Ming Univ, Sch Med, Inst Pharmacol, Taipei 112304 - Taiwan

• Tipo de documento: Artigo Científico
• Fonte: American Journal of Human Genetics; v. 108, n. 1, p. 115-133, JAN 7 2021.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
• Beneficiário: Alexander Augusto de Lima Jorge
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/10893-6 - Avaliação prospectiva do uso do sequenciamento exômico na investigação etiológica de pacientes sindrômicos com baixa estatura sem diagnóstico clínico
• Beneficiário: Bruna Lucheze Freire
• Modalidade de apoio: Bolsas no Brasil - Doutorado