Abstract
Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia and dental abnormalities. This disease is mainly caused by heterozygous mutations in RUNX2, a gene that encodes an osteoblast-specific transcription factor. In the present study, mutational analyses of RUNX2 gene were performed on four unrelated Chinese patients with CCD. Four different RUNX2 mutations were detected in these patients, including one nonsense mutation (c.199C>T p.Q67X) and three missense mutations (c.338T>G p.L113R, c.557G>C p.R186T and c.673C>T p.R225W). Among them, two mutations (c.199C>T p.Q67X and c.557G>C p.R186T) were novel and the other two had been reported in previous literatures. Except for Q67X mutation located in the Q/A domain, other three mutations were clustered within the highly conserved Runt domain. Green fluorescent protein (GFP) and RUNX2 fusion protein analyses in vitro showed that nuclear accumulation of RUNX2 protein was disturbed by Q67X mutation, while the other two mutations (c.338T>G p.L113R and c.557G>C p.R186T) had no effects on the subcellular distribution of RUNX2. Luciferase reporter assay demonstrated that all the three novel RUNX2 mutations significantly reduced the transactivation activity of RUNX2 on osteocalcin promoter. Our findings enrich the evidence of molecular genetics that the mutations of RUNX2 gene are responsible for CCD.
Highlights
Cleidocranial dysplasia (CCD, OMIM 119600) is an autosomal-dominantly inherited skeletal disorder, which is characterized by persistently open or delayed closure of cranial sutures, hypoplastic or aplastic clavicles, and many dental abnormalities, including delayed eruption of secondary teeth accompanied by retained primary teeth, and multiple supernumerary teeth [1]
All the detected novel mutations were introduced into wild-type pEGFPN1-RUNX2 construct by mutagenesis, the constructs were transiently transfected into MC3TC-E1 cells
Four CCD patients were included in this study and four different heterozygous mutations in the RUNX2 gene were identified
Summary
Cleidocranial dysplasia (CCD, OMIM 119600) is an autosomal-dominantly inherited skeletal disorder, which is characterized by persistently open or delayed closure of cranial sutures, hypoplastic or aplastic clavicles, and many dental abnormalities, including delayed eruption of secondary teeth accompanied by retained primary teeth, and multiple supernumerary teeth [1]. Hand abnormalities could be observed in some patients, such as brachydactyly, tapering fingers, and short, broad thumbs [1]. Individuals with CCD are shorter than their unaffected sibs and are more likely to have other skeletal/orthopedic problems such as pes planus, genu valgum, and scoliosis [1, 2]. The spectrum of phenotypes is dramatically variable even within families, ranging from only mildly affected patients with dental abnormalities to severely affected ones with severe defects in skeletal system [3, 4].
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