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

Am J Hum Genet. 2021 Jan 7;108(1):115-133. doi: 10.1016/j.ajhg.2020.11.015. Epub 2020 Dec 11.


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.

Keywords: BMP; BMP receptors; SCUBE; bone morphogenetic protein; genomic sequencing; intracellular signaling; mechanism of disease; morphogenesis; skeletal development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Morphogenetic Protein 4 / metabolism
  • Bone Morphogenetic Proteins / metabolism
  • Bone and Bones / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Developmental Disabilities / metabolism*
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • MCF-7 Cells
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Osteogenesis / physiology*
  • Signal Transduction / physiology*


  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • SCUBE3 protein, human