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

Genomics England Research Consortium

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)115-133
Number of pages19
JournalAmerican Journal of Human Genetics
Volume108
Issue number1
DOIs
Publication statusPublished - Jan 7 2021

Keywords

  • BMP
  • BMP receptors
  • bone morphogenetic protein
  • genomic sequencing
  • intracellular signaling
  • mechanism of disease
  • morphogenesis
  • SCUBE
  • skeletal development

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling'. Together they form a unique fingerprint.

Cite this