ZFIN ID: ZDB-PUB-191207-1
EFTUD2 gene deficiency disrupts osteoblast maturation and inhibits chondrocyte differentiation via activation of the p53 signaling pathway
Wu, J., Yang, Y., He, Y., Li, Q., Wang, X., Sun, C., Wang, L., An, Y., Luo, F.
Date: 2019
Source: Human genomics   13: 63 (Journal)
Registered Authors: Jing, Wu, Li, Qiang
Keywords: Chondrocyte, Developmental delay, EFTUD2, Mandibulofacial dysostosis with microcephaly, Osteoblast, TP53 signaling pathway, Zebrafish
MeSH Terms:
  • Animals
  • Base Sequence
  • Bone and Bones/embryology
  • Bone and Bones/pathology
  • Cartilage/embryology
  • Cartilage/pathology
  • Cell Differentiation*
  • Cell Line
  • Child, Preschool
  • Chondrocytes/metabolism
  • Chondrocytes/pathology*
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mutation/genetics
  • Osteoblasts/metabolism
  • Osteoblasts/pathology*
  • Pedigree
  • Peptide Elongation Factors/deficiency*
  • Peptide Elongation Factors/genetics*
  • Peptide Elongation Factors/metabolism
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Ribonucleoprotein, U5 Small Nuclear/deficiency*
  • Ribonucleoprotein, U5 Small Nuclear/genetics*
  • Ribonucleoprotein, U5 Small Nuclear/metabolism
  • Signal Transduction*
  • Time Factors
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish
PubMed: 31806011 Full text @ Hum. Genomics
Mandibulofacial dysostosis with microcephaly (MFDM) is characteristic of multiple skeletal anomalies comprising craniofacial anomalies/dysplasia, microcephaly, dysplastic ears, choanal atresia, and short stature. Heterozygous loss of function variants of EFTUD2 was previously reported in MFDM; however, the mechanism underlying EFTUD2-associated skeletal dysplasia remains unclear.
We identified a novel frameshift variant of EFTUD2 (c.1030_1031delTG, p.Trp344fs*2) in an MFDM Chinese patient with craniofacial dysmorphism including ear canal structures and microcephaly, mild intellectual disability, and developmental delay. We generated a zebrafish model of eftud2 deficiency, and a consistent phenotype consisting of mandibular bone dysplasia and otolith loss was observed. We also showed that EFTUD2 deficiency significantly inhibited proliferation, differentiation, and maturation in human calvarial osteoblast (HCO) and human articular chondrocyte (HC-a) cells. RNA-Seq analysis uncovered activated TP53 signaling with increased phosphorylation of the TP53 protein and upregulation of five TP53 downstream target genes (FAS, STEAP3, CASP3, P21, and SESN1) both in HCO and in eftud2-/- zebrafish. Additionally, inhibition of p53 by morpholino significantly reduced the mortality of eftud2-/- larvae.
Our results confirm a novel de novo variant of the EFTUD2 gene and suggest that EFTUD2 may participate in the maturation and differentiation of osteoblasts and chondrocytes, possibly via activation of the TP53 signaling pathway. Thus, mutations in this gene may lead to skeletal anomalies in vertebrates.