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; Maroofian, Reza; Beetz, Christian; van Duyvenvoorde, Hermine; Dentici, Maria; Lauffer, Peter; Vallian, Sadeq; Ciolfi, Andrea; Pizzi, Simone; Bauer, Peter; Gruening, Nana-Maria; Bellacchio, Emanuele; Del Fattore, Andrea; Petrini, Stefania; Shaheen, Ranad; Tiosano, Dov; Halloun, Rana; Ben Pode-Shakked, Ben; Albayrak, HATİCE; Isik, Emreguel; Wit, Jan; Dittrich, Marcus; Freire, Bruna; Bertola, Debora; Jorge, Alexander; Barel, Ortal; Sabir, Ataf; Al Tenaiji, Amal; Taji, Sulaima; Al-Sannaa, Nouriya; Al-Abdulwahed, Hind; Digilio, Maria; Irving, Melita; Anikster, Yair; Bhavani, Gandham; Girisha, Katta; Haaf, Thomas; Taylor, Jenny; Dallapiccola, Bruno; Alkuraya, Fowzan; Yang, Ruey-Bing; Tartaglia, Marco

doi:10.1016/j.ajhg.2020.11.015

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

Lin Y., Niceta M., Muto V., Vona B., Pagnamenta A. T., Maroofian R., ...Daha Fazla

AMERICAN JOURNAL OF HUMAN GENETICS, cilt.108, sa.1, ss.115-133, 2021 (SCI-Expanded, Scopus)

Yayın Türü: Makale / Tam Makale
Cilt numarası: 108 Sayı: 1
Basım Tarihi: 2021
Doi Numarası: 10.1016/j.ajhg.2020.11.015
Dergi Adı: AMERICAN JOURNAL OF HUMAN GENETICS
Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, International Bibliography of Social Sciences, BIOSIS, CAB Abstracts, Chemical Abstracts Core, CINAHL, EMBASE, MEDLINE, Veterinary Science Database
Sayfa Sayıları: ss.115-133
Ankara Üniversitesi Adresli: Evet

Özet

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.