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

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

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

Journal

American journal of human genetics

ISSN: 1537-6605

Titre abrégé: Am J Hum Genet

Pays: United States

ID NLM: 0370475

Informations de publication

Date de publication:
07 01 2021

Historique:

received: 23 09 2020

accepted: 20 11 2020

pubmed: 15 12 2020

medline: 3 2 2021

entrez: 14 12 2020

Statut: ppublish

Résumé

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

Identifiants

DOI: 10.1016/j.ajhg.2020.11.015 PMID: 33308444 PMC: PMC7820739

pubmed: 33308444

pii: S0002-9297(20)30412-2

doi: 10.1016/j.ajhg.2020.11.015

pmc: PMC7820739

pii:

doi:

Substances chimiques

Bone Morphogenetic Protein 2 0

Bone Morphogenetic Protein 4 0

Bone Morphogenetic Proteins 0

Calcium-Binding Proteins 0

Intercellular Signaling Peptides and Proteins 0

SCUBE3 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

115-133

Subventions

Organisme : Wellcome Trust

Pays : United Kingdom