Mandibulofacial dysostosis with microcephaly (MFDM) is characteristic of multiple skeletal anomalies comprising craniofacial anomalies/dysplasia, microcephaly, dysplastic ears, choanal atresia and short stature. Loss of function mutations of EFTUD2 were previously reported in MFDM, however, the mechanism underlying EFTUD2-associated skeletal dysplasia remains unclear. Here, we identified a novel frameshift mutation of EFTUD2 in a MFDM Chinese patient with craniofacial dysmorphism including ear canal structures and microcephaly, mild intellectual disability and developmental delay. We have generated a zebrafish model of eftud2 deficiency and consistent phenotype of mandibular bone dysplasia and otolith loss were observed. We have also shown that EFTUD2 deficiency significantly inhibited proliferation, differentiation and maturation in human calvarial osteoblasts (HCO) and articular chondrocytes (HC-a). RNA-Seq analysis uncovered activated TP53 signaling with increased phosphorylation of 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. Together, our results suggest that EFTUD2 may participate in the maturation of osteoblast and is necessary for chondrocyte differentiation, possibly via activation of the TP53 signaling, and thereby, leading to skeletal anomalies in vertebrates.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology