A novel frameshift mutation in the NMTS domain of RUNX2 in a Chinese family with cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant heritable skeletal disorder, caused by heterozygous mutations of Runx2. This study aimed to investigate the Runx2 mutation in a Chinese family with CCD and study the pathogenesis of the mutational Runx2 gene. A 29-year-old male was diagnosed as proband of CCD based on the clinical findings, which show hypoplastic clavicles, underdeveloped maxilla, supernumerary teeth, and retention of deciduous dentition. Sanger sequencing showed the presence of a novel deletion mutation, c.1271delC, in exon 7 within the nuclear matrix targeting signal domain of the proband’s Runx2 gene. We did not find any mutations in the unaffected family members or 200 healthy random individuals. In vitro analysis revealed significantly increased expression of the p.P424HfsTer39 variant at the protein level compared to wild-type RUNX2 protein. The study of the Green fluorescent protein fusion indicated that the 1271delC mutation affected the nuclear accumulation of RUNX2 protein. The findings showed that the 1271delC introduced a novel stop codon at codon 483, which had caused a truncated RUNX2 protein and impaired subcellular localization of RUNX2, resulting in CCD pathogenesis. The results broaden the spectrum of the mutation in the Runx2 gene and offer the new evidence to study the pathogenesis of Runx2 gene mutations.