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Gene-Expression Analysis Identifies IGFBP2 Dysregulation in Dental Pulp Cells From Human Cleidocranial Dysplasia.

ABSTRACT: Cleidocranial dysplasia (CCD) is an autosomal dominant disorder affecting osteoblast differentiation, chondrocyte maturation, skeletal morphogenesis, and tooth formation. Dental phenotype in CCD include over-retained primary teeth, failed eruption of permanent teeth, and supernumerary teeth. The underlying mechanism is unclear. We previously reported one CCD patient with allelic RUNX2 deletion (CCD-011). In the current study, we determined the transcriptomic profiles of dental pulp cells from this patient compared to one sex-and-age matched non-affected individual. Next Generation RNA sequencing revealed that 60 genes were significantly dysregulated (63% upregulated and 27% downregulated). Among them, IGFBP2 (insulin-like growth factor binding protein-2) was found to be upregulated more than twofold in comparison to control cells. Stable overexpression of RUNX2 in CCD-011 pulp cells resulted in the reduction of IGFBP2. Moreover, ALPL expression was up-regulated in CCD-011 pulp cells after introduction of normal RUNX2. Promoter analysis revealed that there are four proximal putative RUNX2 binding sites in -1.5 kb IGFBP2 promoter region. Relative luciferase assay confirmed that IGFBP2 is a direct target of RUNX2. Immunohistochemistry demonstrated that IGFBP2 was expressed in odontoblasts but not ameloblasts. This report demonstrated the importance of RUNX2 in the regulation of gene profile related to dental pulp cells and provided novel insight of RUNX2 into the negative regulation of IGFBP2.

SUBMITTER: Greene SL

PROVIDER: S-EPMC5974155 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Gene-Expression Analysis Identifies IGFBP2 Dysregulation in Dental Pulp Cells From Human Cleidocranial Dysplasia.

Greene Stephen L SL Mamaeva Olga O Crossman David K DK Lu Changming C MacDougall Mary M

Frontiers in genetics 20180523

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder affecting osteoblast differentiation, chondrocyte maturation, skeletal morphogenesis, and tooth formation. Dental phenotype in CCD include over-retained primary teeth, failed eruption of permanent teeth, and supernumerary teeth. The underlying mechanism is unclear. We previously reported one CCD patient with allelic <i>RUNX2</i> deletion (CCD-011). In the current study, we determined the transcriptomic profiles of dental pulp cells ...[more]

PMID: 29875795

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Project description:ObjectivesCleidocranial dysplasia (CCD) is a skeletal disorder affecting cranial sutures, teeth, and clavicles, and is associated with the RUNX2 mutations. Although numerous patients have been described, a direct genotype-phenotype correlation for RUNX2 has been difficult to establish. Further cases must be studied to understand the clinical and genetic spectra of CCD. To characterize detailed phenotypes and identify variants causing CCD in five unrelated patients and their family members.MethodologyClinical and radiographic examinations were performed. Genetic variants were identified by exome and Sanger sequencing, data were analyzed by bioinformatics tools.ResultsThree cases were sporadic and two were familial. Exome sequencing successfully detected the heterozygous pathogenic RUNX2 variants in all affected individuals. Three were novel, comprising a frameshift c.739delA (p.(Ser247Valfs*)) in exon 6 (Patient-1), a nonsense c.901C>T (p.(Gln301*)) in exon 7 (Patient-2 and affected mother), and a nonsense c.1081C>T (p.(Gln361*)) in exon 8 (Patient-3). Two previously reported variants were missense: the c.673C>T (p.(Arg225Trp)) (Patient-4) and c.674G>A (p.(Arg225Gln)) (Patient-5) in exon 5 within the Runt homology domain. Patient-1, Patient-2, and Patient-4 with permanent dentition had thirty, nineteen, and twenty unerupted teeth, respectively; whereas Patient-3 and Patient-5, with deciduous dentition, had normally developed teeth. All patients exhibited typical CCD features, but the following uncommon/unreported phenotypes were observed: left fourth ray brachymetatarsia (Patient-1), normal clavicles (Patient-2 and affected mother), phalangeal malformations (Patient-3), and normal primary dentition (Patient-3, Patient-5).ConclusionsThe study shows that exome sequencing is effective to detect mutation across ethnics. The two p.Arg225 variants confirm that the Runt homology domain is vital for RUNX2 function. Here, we report a new CCD feature, unilateral brachymetatarsia, and three novel truncating variants, expanding the phenotypic and genotypic spectra of RUNX2 , as well as show that the CCD patients can have normal deciduous teeth, but must be monitored for permanent teeth anomalies.

Dataset Information

Gene-Expression Analysis Identifies IGFBP2 Dysregulation in Dental Pulp Cells From Human Cleidocranial Dysplasia.

Publications

Gene-Expression Analysis Identifies IGFBP2 Dysregulation in Dental Pulp Cells From Human Cleidocranial Dysplasia.

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