Functional analysis of novel <i>RUNX2</i> mutations identified in patients with cleidocranial dysplasia

Hordyjewska-Kowalczyk, Ewa; Sowińska‐Seidler, Anna; Olech, Ewelina M.; Socha, Magdalena; Glazar, Renata; Kruczek, Anna; Latos‐Bieleńska, Anna; Tylzanowski, Przemko; Jamsheer, Aleksander

doi:10.1111/cge.13610

Cited by 19 publications

(10 citation statements)

References 44 publications

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“…Runx2 is a vital regulator in bone development and is essential for osteoblast differentiation. Mutation of Runx2 is related to skeletal malformation syndromes, including cleidocranial dysplasia (CCD) [ 41 , 42 ]. Runx2 knockout mice lose all intramembranous and endochondral osteogenesis and die after birth due to lack of mineralization in the chest region, which results in breathing difficulties, even in the presence of BMP [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

HIF1α Promotes BMP9-Mediated Osteoblastic Differentiation and Vascularization by Interacting with CBFA1

Liu

Wang

et al. 2022

BioMed Research International

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Bone morphogenetic protein 9 (BMP9) as the most potent osteogenic molecule which initiates the differentiation of stem cells into the osteoblast lineage and regulates angiogenesis, remains unclear how BMP9-regulated angiogenic signaling is coupled to the osteogenic pathway. Hypoxia-inducible factor 1α (HIF1α) is critical for vascularization and osteogenic differentiation and the CBFA1, known as runt-related transcription factor 2 (Runx2) which plays a regulatory role in osteogenesis. This study investigated the combined effect of HIF1α and Runx2 on BMP9-induced osteogenic and angiogenic differentiation of the immortalized mouse embryonic fibroblasts (iMEFs). The effect of HIF1α and Runx2 on the osteogenic and angiogenic differentiation of iMEFs was evaluated. The relationship between HIF1α- and Runx2-mediated angiogenesis during BMP9-regulated osteogenic differentiation of iMEFs was evaluated by ChIP assays. We demonstrated that exogenous expression of HIF1α and Runx2 is coupled to potentiate BMP9-induced osteogenic and angiogenic differentiation both in vitro and animal model. Chromatin immunoprecipitation assays (ChIP) showed that Runx2 is a downstream target of HIF1α that regulates BMP9-mediated osteogenesis and angiogenic differentiation. Our findings reveal that HIF1α immediately regulates Runx2 and may originate an essential regulatory thread to harmonize osteogenic and angiogenic differentiation in iMEFs, and this coupling between HIF1α and Runx2 is essential for bone healing.

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Section: Discussionmentioning

confidence: 99%

HIF1α Promotes BMP9-Mediated Osteoblastic Differentiation and Vascularization by Interacting with CBFA1

Liu

Wang

et al. 2022

BioMed Research International

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“…Till recent years, almost 194 causative mutations in RUNX2 have been identified, and this number is still rising (Otto et al 2002). However, RUNX2 mutations can be found only in two-third of patients with CCD, and 30%-40% of cases are triggered by novel mutations (Hordyjewska-Kowalczyk et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Background Cleidocranial 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. Objective Identification and functional characterization of RUNX2 mutation associated with CCD. Methods We 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. Results We 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. 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.

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“…The clinical diagnosis can be made based on a set of physical and radiological characteristics, which include underdeveloped or absent clavicles, delayed closure of fontanelles, and dental and maxillofacial abnormalities [1,2]. As the most well-known genetic predisposing factor for this disease, mutational analysis of the Runt-related transcription factor 2 RUNX2 gene may be utilized for diagnostic con rmation [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Detection and diagnosis of cleidocranial dysplasia by panoramic radiography

Shi

Liu

et al. 2022

Preprint

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BackgroundThe purpose of this study was to illustrate and quantify the maxillofacial bone abnormalities detected on panoramic radiographs from a group of Chinese patients with cleidocranial dysplasia (CCD) and to provide a series of diagnostic references for dentists to indicate the presence of disease and help in making an early and accurate diagnosis.Materials and methodsThe dental panoramic radiographs of thirty CCD patients aged 11 to 45 years (18 males and 12 females) were examined retrospectively. The dentition states, including supernumerary teeth and impacted teeth, were recorded. Twelve quantified measurements were adopted to determine the abnormalities of maxillofacial bones, including the degree of the zygomatic arch downward bend, bicondylar breadth, ramal height, mandibular height, mandibular aspect ratio, mandibular body height, condylar height, coronoid height, distance between the coronoid process and the condyle, bigonial width, gonial angle and best-fit gonial circle diameter. The Wilcoxon rank-sum test was used to compare the findings of the CCD patients with those of their matched controls (n=300).ResultsSupernumerary teeth were detected in 27 patients (90.0%), and all 30 patients presented impacted teeth. Compared to the matched controls, the CCD patients had a significantly larger degree of zygomatic arch downward bend (ZAD), a larger diameter of the best-fit gonial circle (BGC), and a shorter distance between the coronoid process and the condyle (DCC) in panoramic radiographs (P<0.001). According to the reference interval established from the 5th or 95th percentile of the measurements in the control group, ZAD less than 6.90 mm, DDC greater than 22.37 mm and BGC greater than 52.41 mm were significantly associated with the CCD features identified. Other panoramic measurements were not significantly different between the two groups.ConclusionsIn this study, we identified some featured radiographic parameters of maxillofacial bones in CCD patients. These features can be recognized in commonly used dental radiographs and therefore may provide valuable information for the early diagnosis and treatment of CCD.

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Functional analysis of novel RUNX2 mutations identified in patients with cleidocranial dysplasia

Cited by 19 publications

References 44 publications

HIF1α Promotes BMP9-Mediated Osteoblastic Differentiation and Vascularization by Interacting with CBFA1

HIF1α Promotes BMP9-Mediated Osteoblastic Differentiation and Vascularization by Interacting with CBFA1

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

Detection and diagnosis of cleidocranial dysplasia by panoramic radiography

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