Identification a novel de novo RUNX2 frameshift mutation associated with cleidocranial dysplasia

Lei Gong,Shouyu Wang,Feng Han,Jiaojiao Yang,Yujing Sun,Bekzod Odilov,Fuqiang Liu,Xiaolin Zuo,Xinguo Hou,Jianmin Ren,Ningxin Zhang

doi:10.1007/s13258-022-01229-w

Abstract

BackgroundCleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in runt-related transcription factor 2 (RUNX2) gene.ObjectiveIdentification and functional characterization of RUNX2 mutation associated with CCD.MethodsWe performed genetic testing of a patient with CCD using whole exome sequencing and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay.ResultsWe found a novel RUNX2 frameshift mutation, c.1550delT (p.Trp518Glyfs*60). Both mutant RUNX2 and wild-type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter.ConclusionsWe explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding suggests that the VWRPY domain may play a key role in RUNX2 transactivation ability.

Highlights

Cleidocranial dysplasia (CCD), referred as a Scheuthauer syndrome, is a rare autosomal dominantly inherited disorder which is represented by various skeletal abnormalities (Lotlikar et al 2018)
Several studies have revealed that CCD development is strongly linked with different mutations affecting runtrelated transcription factor 2 (RUNX2) gene (Jaruga et al 2016; Xuan et al 2008), which is a transcription factor involved in osteoblastic differentiation and skeletal morphogenesis
RUNX2 gene comprises Q/A domain on N-terminal part, RUNT domain which is crucial for DNA-binding to a specialized motif and heterodimerization with core-binding factor subunit beta (CBFβ) (Zhang et al 2017), as well as proline/serine/threonine-rich (PST) domain on its C-terminus (Yoshida et al 2002)

Summary

Introduction

Cleidocranial dysplasia (CCD), referred as a Scheuthauer syndrome, is a rare autosomal dominantly inherited disorder which is represented by various skeletal abnormalities (Lotlikar et al 2018). Clinical features of CCD is diverse and involves short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles, multiple dental defects such as teeth hypoplasia, delayed primary teeth exfoliation, prolonged eruption of permanent teeth and malocclusion (Konishi et al 2019). Other skeletal abnormalities, such as hypoplastic iliac wings, distal phalanx dysplasia, knock-knees and malformations of spine can be observed (Farrow et al 2018). Conclusions We explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding suggests that the VWRPY domain may play a key role in RUNX2 transactivation ability

Methods

Results

Conclusion