A Novel RUNX2 Mutation in Cleidocranial Dysplasia Patients

Xuan, Dongying; Shi, Li; Zhang, Xiong; Lin, Lixin; Chun-xian, Wang; Zhang, Jincai

doi:10.1007/s10528-008-9184-4

Cited by 7 publications

(12 citation statements)

References 7 publications

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“…B: The schematic shows functional domains and the mutation sites of RUNX2 in CCD patients. Mutations reported in previous studies [Otto et al, 2002; Yoshida et al, 2002; Tessa et al, 2003; Kim et al, 2006; Pal et al, 2007; Xuan et al, 2008; Li et al, 2009; Zhang et al, 2009; Cardoso et al, 2010; Gao et al, 2010; Wang et al, 2010] are indicated below the structure of RUNX2 protein (the 521 amino acids isoform starting with MASNS). The new mutation E366X identified in the present study is indicated above the structure.…”

Section: Resultsmentioning

confidence: 96%

“…DNA was extracted from blood samples with the QIAamp Blood Kit (Qiagen). Exons 0–7 of the RUNX2 gene were amplified from genomic DNA and sequenced as previously outlined [Xuan et al, 2008]. Briefly, the PCR reaction was performed with a 5 min denaturation at 94°C, followed by 25 cycles, each with denaturation at 94°C for 30 s, primer annealing for 30 s at different temperature respectively (Table I), and product extension at 72°C for 1 min.…”

Section: Methodsmentioning

confidence: 99%

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Effect of cleidocranial dysplasia‐related novel mutation of RUNX2 on characteristics of dental pulp cells and tooth development

Xuan

Sun

Yan

et al. 2010

J of Cellular Biochemistry

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Cleidocranial dysplasia (CCD) is an autosomal-dominant disorder caused by a lack of function of one or more alleles of the RUNX2 gene. Mutations of the RUNX2 gene were analyzed in a family with CCD, and a novel nonsense mutation was identified, c. 1096G > T, p.E366X, which was predicted to cause a number of potential dysfunctions. Western blot analysis showed that the novel mutation created a shortened protein product, which lost 155 aa in the C-terminal domain. The mutant protein was detected to be localized mostly in the cytoplasm, not in the nucleus, which demonstrated that transport of the RUNX2 protein into the nucleus was disturbed by the p.E366X mutation. For the first time, RUNX2(+/m) dental pulp cells (DPCs) were isolated from two permanent incisors of the CCD patient. Compared to RUNX2(+/+) controls, RUNX2(+/m) DPCs presented an impeded progression from the G1 to the S phase in the cell cycle, a lower rate of proliferation, weaker ability of calcification, and distinct ultrastructure. More interestingly, the ultrastructural analysis and energy dispersive X-ray spectrometry (EDS) analysis showed that the CCD tooth exhibited insufficient mineralization of enamel and dentin. This study suggests that the truncated RUNX2 mutant protein may be responsible for the alterations of RUNX2(+/m) DPCs, and RUNX2 gene may be involved in dental development by affecting the cell growth and differentiation, which provides new insights into understanding of dental abnormalities in CCD patients.

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Section: Resultsmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Effect of cleidocranial dysplasia‐related novel mutation of RUNX2 on characteristics of dental pulp cells and tooth development

Xuan

Sun

Yan

et al. 2010

J of Cellular Biochemistry

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“…The type and location of specific mutations within the RUNX2 gene impact the expressivity of the CCD phenotypic findings, thus correlating the genetic variations in the corresponding gene with the clinical manifestations of the syndrome [9]. …”

Section: Introductionmentioning

confidence: 99%

A 13-year-old caucasian boy with cleidocranial dysplasia: a case report

Kolokitha

Ioannidou

2013

BMC Res Notes

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BackgroundCleidocranial dysplasia (CCD) is a rare congenital autosomal dominant skeletal disorder. The disorder is caused by heterozygosity of mutations in human RUNX2, which is present on the short arm of chromosome 6p21. The incidence of CCD is one per million births. CCD appears spontaneously with no apparent genetic cause in approximately 40% of affected patients, and one in three patients has unaffected parents. The most prevalent features associated with CCD are aplastic or hypoplastic clavicles, supernumerary teeth, failed eruption of permanent teeth, and a hypoplastic maxilla.Case presentationA 13-year-old Caucasian boy presented with a chief complaint of delayed eruption of the permanent anterior teeth. The patient was subsequently diagnosed with CCD based on the clinical examination, panoramic X-ray, anterior-posterior and lateral cephalogram, and chest radiograph findings. The details of this case are herein reported because of the extremely low incidence of this disorder.ConclusionsCCD is of clinical importance in dentistry and medicine because it affects the bones and teeth and is characterized by many changes in skeletal patterning and growth. Particularly in dentistry, CCD is of great clinical significance because is associated with delayed ossification of the skull sutures, delayed exfoliation of the primary teeth, lack of permanent teeth eruption, multiple supernumerary teeth, and morphological abnormalities of the maxilla and mandible. Patients with CCD seek treatment mainly for dental problems. Knowledge of the pathogenesis, clinical characteristics, and diagnostic tools of CCD will enable clinicians to render the appropriate treatment to improve function and aesthetics. Early diagnosis of CCD is crucial for timely initiation of an appropriate treatment approach.

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“…(12) Abnormalities in RUNX2 function can lead to cleidocranial dysplasia (CCD), in which there is defective ossification of the cranial bones with large fontanels and delayed closing of the sutures with complete or partial absence of the clavicles. (13)(14)(15)(16)(17)(18)(19) Mice with homozygous mutations in RUNX2 cannot survive after birth owing to breathing defects caused by the absence of ossification of the ribs. (20,21) The functions of RUNX2 and SOX9 are controlled by transcriptional and posttranscriptional regulation, including ubiquitination, phosphorylation, and acetylation.…”

Section: Introductionmentioning

confidence: 99%

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Cheng

Genever

2010

Journal of Bone and Mineral Research

133

112

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Mesenchymal stem cell differentiation is controlled by the cooperative activity of a network of signaling mechanisms. Among these, RUNX2 and SOX9 are the major transcription factors for osteogenesis and chondrogenesis, respectively. Their expression is overlapped both temporally and spatially during embryogenesis. Here we have demonstrated that RUNX2 and SOX9 physically interact in intact cells and have confirmed that SOX9 can inhibit the transactivation of RUNX2. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dosedependent degradation of RUNX2. Although RUNX2 is normally degraded by the ubiquitin-proteasome pathway, we found that SOX9-mediated degradation was proteasome-independent but phosphorylation-dependent and required the presence of the RUNX2 Cterminal domain, which contains a nuclear matrix targeting sequence (NMTS). Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed b-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown. Consequently, the mechanisms by which SOX9 regulates RUNX2 function may underlie broader signaling pathways that can influence osteochondrogenesis and mesenchymal fate. ß

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A Novel RUNX2 Mutation in Cleidocranial Dysplasia Patients

Cited by 7 publications

References 7 publications

Effect of cleidocranial dysplasia‐related novel mutation of RUNX2 on characteristics of dental pulp cells and tooth development

Effect of cleidocranial dysplasia‐related novel mutation of RUNX2 on characteristics of dental pulp cells and tooth development

A 13-year-old caucasian boy with cleidocranial dysplasia: a case report

SOX9 determines RUNX2 transactivity by directing intracellular degradation

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