RUNX2 mutations in cleidocranial dysplasia

Lee, K.-E.; Seymen, Figen; Ko, Jung Min; Yıldırım, Mehmet; Tuna, Elif Bahar; Gençay, Koray; Kim, J.-W.

doi:10.4238/2013.october.15.5

Cited by 38 publications

(31 citation statements)

References 32 publications

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“…Mutations in Runx2 have been identified in patients with cleidocranial dysplasia, which is a rare autosomal dominant skeletal dysplasia characterized by delayed closure of the cranial sutures [25], and Runx2 has been shown to regulate the expressions of type I collagen and OC [26]. In this study, we found that both the mRNA and protein levels of Runx2 were increased in the bovine CP compound-treated cells compared with the CN cells, demonstrating that CP compounds promoted the differentiation of osteoblasts by upregulating the level of Runx2 expression.…”

Section: Discussionmentioning

confidence: 99%

Bovine Collagen Peptides Compounds Promote the Proliferation and Differentiation of MC3T3-E1 Pre-Osteoblasts

et al. 2014

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ObjectiveCollagen peptides (CP) compounds, as bone health supplements, are known to play a role in the treatment of osteoporosis. However, the molecular mechanisms of this process remain unclear. This study aimed to investigate the effects of bovine CP compounds on the proliferation and differentiation of MC3T3-E1 cells.MethodsMouse pre-osteoblast cell line MC3T3-E1 subclone 4 cells were treated with bovine CP compounds. Cell proliferation was analyzed by MTT assays and the cell cycle was evaluated by flow cytometry scanning. Furthermore, MC3T3-E1 cell differentiation was analyzed at the RNA level by real-time PCR and at the protein level by western blot analysis for runt-related transcription factor 2 (Runx2), a colorimetric p-nitrophenyl phosphate assay for alkaline phosphatase (ALP), and ELISA for osteocalcin (OC). Finally, alizarin red staining for mineralization was measured using Image Software Pro Plus 6.0.ResultsCell proliferation was very efficient after treatment with different concentrations of bovine CP compounds, and the best concentration was 3 mg/mL. Bovine CP compounds significantly increased the percentage of MC3T3-E1 cells in G2/S phase. Runx2 expression, ALP activity, and OC production were significantly increased after treatment with bovine CP compounds for 7 or 14 days. Quantitative analyses with alizarin red staining showed significantly increased mineralization of MC3T3-E1 cells after treatment with bovine CP compounds for 14 or 21 days.ConclusionsBovine CP compounds increased osteoblast proliferation, and played positive roles in osteoblast differentiation and mineralized bone matrix formation. Taking all the experiments together, our study indicates a molecular mechanism for the potential treatment of osteoarthritis and osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Bovine Collagen Peptides Compounds Promote the Proliferation and Differentiation of MC3T3-E1 Pre-Osteoblasts

et al. 2014

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“…Depending on the spacing of the probes, losses or gains encompassing a single or several full genes or even a single exon can be detected [Coe et al, 2007;Boone et al, 2010]. Applying this technique to patients with craniosynostosis, CNVs involving the GLI3 , IHH , MMP23 , RUNX2 , SKI , and TCF12 genes were identified [Gajecka et al, 2005;de Pater et al, 2006;Mefford et al, 2010;Hurst et al, 2011;Carmignac et al, 2012;Doyle et al, 2012;Lee et al, 2013;Goos et al, 2016;Dinçsoy et al, 2017]. Such CNVs alter the dosage of putative candidate genes and thus affect the phenotype of the carrier by a dominant mechanism.…”

Section: Craniosynostosis Gene Identificationmentioning

confidence: 99%

Structural Genome Variations Related to Craniosynostosis

Poot¹

2018

Mol Syndromol

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Craniosynostosis refers to a condition during early development in which one or more of the fibrous sutures of the skull prematurely fuse by turning into bone, which produces recognizable patterns of cranial shape malformations depending on which suture(s) are affected. In addition to cases with isolated cranial dysmorphologies, craniosynostosis appears in syndromes that include skeletal features of the eyes, nose, palate, hands, and feet as well as impairment of vision, hearing, and intellectual development. Approximately 85% of the cases are nonsyndromic sporadic and emerge after de novo structural genome rearrangements or single nucleotide variation, while the remainders consist of syndromic cases following mendelian inheritance. By karyotyping, genome wide linkage, and CNV analyses as well as by whole exome and whole genome sequencing, numerous candidate genes for craniosynostosis belonging to the FGF, Wnt, BMP, Ras/ERK, ephrin, hedgehog, STAT, and retinoic acid signaling pathways have been identified. Many of the craniosynostosis-related candidate genes form a functional network based upon protein-protein or protein-DNA interactions. Depending on which node of this craniosynostosis-related network is affected by a gene mutation or a change in gene expression pattern, a distinct craniosynostosis syndrome or set of phenotypes ensues. Structural variations may alter the dosage of one or several genes or disrupt the genomic architecture of genes and their regulatory elements within topologically associated chromatin domains. These may exert dominant effects by either haploinsufficiency, dominant negative partial loss of function, gain of function, epistatic interaction, or alteration of levels and patterns of gene expression during development. Molecular mechanisms of dominant modes of action of these mutations may include loss of one or several binding sites for cognate protein partners or transcription factor binding sequences. Such losses affect interactions within functional networks governing development and consequently result in phenotypes such as craniosynostosis. Many of the novel variants identified by genome wide CNV analyses, whole exome and whole genome sequencing are incorporated in recently developed diagnostic algorithms for craniosynostosis.

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“…The age of onset was 8 years old, and the patient presented with classical bone phenotypes that had appeared in childhood [10]. This mutation was later reported in a teenage Korean patient with sporadic CCD, who also presented with dental and skeletal problems [11]. Those carriers of the RUNX2 p.R225Q mutation reported no neurological complaints; in particular, there were no symptoms or signs of myopathy.…”

Section: Discussionmentioning

confidence: 99%

A limb-girdle myopathy phenotype of RUNX2 mutation in a patient with cleidocranial dysplasia: a case study and literature review

et al. 2017

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BackgroundCleidocranial dysplasia (CCD) is a rare hereditary disorder that arises from heterozygous loss of function mutations in the runt-related transcription factor 2 (RUNX2) gene. As RUNX2 is mainly expressed in osteoblasts, CCD typically affects the skeletal and dental systems. Few studies have investigated RUNX2 mutation effects on non-skeletal systems. Here, we describe limb-girdle myopathy, an uncommon phenotype of CCD, in a patient with a heterozygous missense mutation (p.R225Q) in the RUNX2 gene.Case presentationA 58 year-old man presented with progressive back pain and six months of weakness in the proximal parts of all four limbs. Physical examinations showed that he was short in stature (height, 164.4 cm; weight, 79.1 kg) with a dysmorphic face, including hypertelorism, midface hypoplasia, and chin protrusion. At a young age, he had received orthodontic surgery, due to dental abnormalities. Neurological examinations revealed sloping shoulders, weakness, and atrophy in the proximal areas of the arms, shoulder girdle muscles, and legs. The deep tendon reflex and sensory system were normal. Radiological examinations revealed mild scoliosis, shortened clavicles, and a depressed skull bone, which were consistent with a clinical diagnosis of CCD. Electromyography (EMG) studies showed myogenic polyphasic waves in the deltoid, biceps brachii, and rectus femoris muscles. Instead, the EMG findings were normal in the first dorsal interosseous, tibialis anterior and facial muscles. The EMG findings were compatible with a limb-girdle pattern with facial sparing. The patient’s family history showed his father and eldest daughter with similar dysmorphic faces, skeletal disorders and proximal upper extremity weakness. We sequenced the RUNX2 gene and discovered a heterozygous missense mutation (c.G674A, p.R225Q), which altered the C-terminal end of the RUNX2 protein. This mutation was predicted to inactivate the protein and might affect its interactions with other proteins. This mutation co-segregated with the disease phenotypes in the family.ConclusionsWe described limb-girdle myopathy in a patient with CCD that carried a heterozygous RUNX2 missense mutation. This uncommon phenotype expanded the phenotypic spectrum of the RUNX2 p.R225Q mutation. The role of RUNX2 in myogenic development merits future studies. Our findings remind clinicians that myopathic patients with myopathies combined with facial dysmorphism and shortened clavicles should consider the diagnosis of CCD.

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RUNX2 mutations in cleidocranial dysplasia

Cited by 38 publications

References 32 publications

Bovine Collagen Peptides Compounds Promote the Proliferation and Differentiation of MC3T3-E1 Pre-Osteoblasts

Bovine Collagen Peptides Compounds Promote the Proliferation and Differentiation of MC3T3-E1 Pre-Osteoblasts

Structural Genome Variations Related to Craniosynostosis

A limb-girdle myopathy phenotype of RUNX2 mutation in a patient with cleidocranial dysplasia: a case study and literature review

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