A missense variant in specificity protein 6 (SP6) is associated with amelogenesis imperfecta

Smith, Claire E. L.; Whitehouse, Laura Le.; Poulter, James A.; Hewitt, Laura Wilkinson; Nadat, Fatima; Jackson, Brian R.; Manfield, Iain W.; Edwards, Thomas A.; Rodd, Helen; Inglehearn, Chris F.; Mighell, Alan J.

doi:10.1093/hmg/ddaa041

Cited by 20 publications

(24 citation statements)

References 38 publications

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“…Patients with high expression of KIF21B have been demonstrated to have a poorer prognosis in hepatocellular carcinoma ( Zhao et al, 2020 ) and non-small cell lung cancer ( Sun et al, 2020 ). SP6 is an important gene that regulates odontogenesis, belonging to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains( Aurrekoetxea et al, 2016 ; Smith et al, 2020 ; Nakamura et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and Analysis of the Tumor-Specific mRNA–miRNA–lncRNA Network in Gastric Cancer

Zheng

Wang

Zheng³

et al. 2020

Front. Pharmacol.

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Weighted correlation network analysis (WGCNA) is a statistical method that has been widely used in recent years to explore gene co-expression modules. Competing endogenous RNA (ceRNA) is commonly involved in the cancer gene expression regulation mechanism. Some ceRNA networks are recognized in gastric cancer; however, the prognosisassociated ceRNA network has not been fully identified using WGCNA. We performed WGCNA using datasets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) to identify cancer-associated modules. The criteria of differentially expressed RNAs between normal stomach samples and gastric cancer samples were set at the false discovery rate (FDR) < 0.01 and |fold change (FC)| > 1.3. The ceRNA relationships obtained from the RNAinter database were examined by both the Pearson correlation test and hypergeometric test to confirm the mRNA-lncRNA regulation. Overlapped genes were recognized at the intersections of genes predicted by ceRNA relationships, differentially expressed genes, and genes in cancer-specific modules. These were then used for univariate and multivariate Cox analyses to construct a risk score model. The ceRNA network was constructed based on the genes in this model. WGCNAuncovered genes in the green and turquoise modules are those most associated with gastric cancer. Eighty differentially expressed genes were observed to have potential prognostic value, which led to the identification of 12 prognosis-related mRNAs (KIF15, FEN1, ZFP69B, SP6, SPARC, TTF2, MSI2, KYNU, ACLY, KIF21B, SLC12A7, and ZNF823) to construct a risk score model. The risk genes were validated using the GSE62254 and GSE84433 datasets, with 0.82 as the universal cutoff value. 12 genes, 12 lncRNAs, and 35 miRNAs were used to build a ceRNA network with 86 dysregulated lncRNA-mRNA ceRNA pairs. Finally, we developed a 12-gene signature from both prognosis-related and tumorspecific genes, and then constructed a ceRNA network in gastric cancer. Our findings may provide novel insights into the treatment of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Construction and Analysis of the Tumor-Specific mRNA–miRNA–lncRNA Network in Gastric Cancer

Zheng

Wang

Zheng³

et al. 2020

Front. Pharmacol.

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“…Of the several transcription factors, Msx2 and Sp6 constitute key players of amelogenesis. Both, Msx2 and Sp6 mouse mutants, exhibit enamel hypoplasia, while humans with AI carry mutations in the human homologues of MSX2 or SP6 genes (Satokata et al, 2000;Bei et al, 2004;Suda et al, 2006;Nakamura et al, 2008;Utami et al, 2011;Babajko et al, 2014;Smith et al, 2020). These similarities in function indicate that these two transcription factors may reside in the same developmental pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The Sp6 mutant mice among other phenotypes exhibit enamel hypoplasia (Nakamura et al, 2008;Utami et al, 2011). Recently, in a Caucasian family with autosomal dominant hypoplastic AI, a missense protein change, p.(Ala273Lys), is identified in SP6, the gene encoding the SP6 transcription factor (Smith et al, 2020). The authors have also "identified a potential SP6 binding motif in the AMBN proximal promoter sequence and showed that wildtype (WT) SP6 binds more strongly to it than the mutant protein, " further indicating the important role of Sp6 in amelogenesis (Smith et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, in a Caucasian family with autosomal dominant hypoplastic AI, a missense protein change, p.(Ala273Lys), is identified in SP6, the gene encoding the SP6 transcription factor (Smith et al, 2020). The authors have also "identified a potential SP6 binding motif in the AMBN proximal promoter sequence and showed that wildtype (WT) SP6 binds more strongly to it than the mutant protein, " further indicating the important role of Sp6 in amelogenesis (Smith et al, 2020). Earlier studies indicate that Sp6 promotes amelogenesis in vitro through inhibition of follistatin (Fst) gene which is a soluble extracellular inhibitor of TGFβ superfamily and is involved in differentiation of secretory ameloblasts during tooth development (Ruspita et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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An Msx2-Sp6-Follistatin Pathway Operates During Late Stages of Tooth Development to Control Amelogenesis

Ruspita

Das

Xia³

et al. 2020

Front. Physiol.

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Background: Ameloblasts are epithelially derived cells responsible for enamel formation through a process known as amelogenesis. Amongst the several transcription factors that are expressed during amelogenesis, both Msx2 and Sp6 transcription factors play important role. Msx2 and Sp6 mouse mutants, exhibit similar amelogenesis defects, namely enamel hypoplasia, while humans with amelogenesis imperfecta (AI) carry mutations in the human homologues of MSX2 or SP6 genes. These across species similarities in function indicate that these two transcription factors may reside in the same developmental pathway. In this paper, we test whether they work in a coordinated manner to exert their effect during amelogenesis. Methods: Two different dental epithelial cell lines, the mouse LS8 and the rat G5 were used for either overexpression or silencing of Msx2 or Sp6 or both. Msx2 mutant mouse embryos or pups were used for in vivo studies. In situ hybridization, semiquantitative and quantitative real time PCR were employed to study gene expression pattern. MatInspector was used to identify several potential putative Msx2 binding sites upstream of the murine Sp6 promoter region. Chromatin Immunoprecipitation (chIP) was used to confirm the binding of Msx2 to Sp6 promoter at the putative sites. Results: Using the above methods we identified that (i) Msx2 and Sp6 exhibit overlapping expression in secretory ameloblasts, (ii) Sp6 expression is reduced in the Msx2 mouse mutant secretoty ameloblasts, and (iii) that Msx2, like Sp6 inhibits follistatin expression. Specifically, our loss-of function studies by silencing Msx2 and/or Sp6 in mouse dental epithelial (LS8) cells showed significant downregulation of Sp6 but upregulation of Fst expression. Transient transfection of Msx2 overexpression plasmid,

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“…Isolated AI results from mutations in specific genes ( LAMB3, ENAM, AMBN, ITGB6, AMELX, KLK4, MMP20, WDR72, ODAPH, SLC24A4, FAM83H, DLX3, ARHGAP6, LAMA3, AMTN, ACPT, GPR68, RELT, SP6 ). 1 - 4 AI presents three subtypes: hypoplastic (type I), hypocalcified (type II), and hypomature (type III). 5 The prevalence of AI reaches 1/14 000 in the USA but to date, no existing epidemiologic study has been conducted in France.…”

Section: Introductionmentioning

confidence: 99%

Gingival inflammation, enamel defects, and tooth sensitivity in children with amelogenesis imperfecta: a case-control study

et al. 2020

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Gingival conditions and tooth sensitivity of young patients with amelogenesis imperfecta lack in depth studies. This case-control study aimed to compare (1) the gingival inflammation, the presence of enamel defects, and tooth sensitivity in young patients with and without amelogenesis imperfecta and (2) to investigate if any difference exists between subtypes of amelogenesis imperfecta. Methodology: We compared forty-two participants with amelogenesis imperfecta with forty-two controls matched for age, gender, and the number of examined sites. Based on interview, clinical examination, and intraoral photography, we collected data on periodontal conditions, enamel defects and the presence of tooth sensitivity. Comparison tests were performed to investigate if any difference existed between cases and controls; and among cases, between the different subtypes of amelogenesis imperfecta. We performed a post-hoc analysis for any significant difference observed. Results: We observed more gingival inflammation, enamel defects and tooth sensitivity among cases (all p<0.05). Participants with hypocalcified amelogenesis imperfecta had more gingival inflammation, enamel defects, and tooth sensitivity than patients with the hypoplastic and hypomature subtypes (all p<0.05). After adjustment for dental plaque, gingival inflammation was associated with the presence of amelogenesis imperfecta (OR (95%CI) = 1.14 (1.05; 1.24). p<0.01). Conclusion: Gingival inflammation, enamel defect and tooth sensitivity are more frequently observed among young patients with amelogenesis imperfecta, and more specifically among children with the hypocalcified subtype.

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A missense variant in specificity protein 6 (SP6) is associated with amelogenesis imperfecta

Cited by 20 publications

References 38 publications

Construction and Analysis of the Tumor-Specific mRNA–miRNA–lncRNA Network in Gastric Cancer

Construction and Analysis of the Tumor-Specific mRNA–miRNA–lncRNA Network in Gastric Cancer

An Msx2-Sp6-Follistatin Pathway Operates During Late Stages of Tooth Development to Control Amelogenesis

Gingival inflammation, enamel defects, and tooth sensitivity in children with amelogenesis imperfecta: a case-control study

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