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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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
Total Authors: 47
Affiliation:
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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
Total Affiliations: 32
Document type: Journal article
Source: American Journal of Human Genetics; v. 108, n. 1, p. 115-133, JAN 7 2021.
Web of Science Citations: 1
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. (AU)

FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
Grantee:Alexander Augusto de Lima Jorge
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 18/10893-6 - Prospective evaluation of exome sequencing in the etiological investigation of syndromic short stature patients without clinical diagnosis
Grantee:Bruna Lucheze Freire
Support Opportunities: Scholarships in Brazil - Doctorate