FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome

Basit Öğe Kaydı
dc.contributor.authorWang, Shih-Kai
dc.contributor.authorZhang, Hong
dc.contributor.authorWang, Yin-Lin
dc.contributor.authorLin, Hung-Ying
dc.contributor.authorSeymen, Figen
dc.contributor.authorKoruyucu, Mine
dc.contributor.authorWright, J. Timothy
dc.contributor.authorKim, Jung-Wook
dc.contributor.authorSimmer, James P.
dc.contributor.authorHu, Jan C-C.
dc.date.accessioned2023-05-31T11:53:47Z
dc.date.available2023-05-31T11:53:47Z
dc.date.issued2023en_US
dc.departmentFakülteler, Diş Hekimliği Fakültesi, Çocuk Diş Hekimliği Ana Bilim Dalıen_US
dc.description.abstractAim: Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia, and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK), and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapupal calcifications. Methodology: Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control. Results: Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTCCA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly), and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20, and WNT10A. Enrichment analyses indicated over-representation of gene sets associated with BMP and SMAD signaling pathways. In contrast, GO terms related to inflammation and axon development were under-represented. Among BMP signaling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4, and BMP6 were upregulated, while BMP antagonists GREM1, BMPER, and VWC2 showed decreased expression in ERS dental pulp tissues. Conclusions: Upregulation of BMP signaling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.en_US
dc.identifier.citationWang, S. K., Zhang, H., Wang, Y. L., Lin, H. Y., Seymen, F., Koruyucu, M., ... & Hu, J. C. C. (2023). FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome. International Endodontic Journal, 56(8), 943-954.en_US
dc.identifier.endpage954en_US
dc.identifier.issn0143-2885
dc.identifier.issn1365-2591
dc.identifier.issue8en_US
dc.identifier.scopus2-s2.0-85159302273
dc.identifier.scopusqualityQ1
dc.identifier.startpage943en_US
dc.identifier.urihttps://hdl.handle.net/20.500.12939/3498
dc.identifier.volume56en_US
dc.identifier.wosWOS:000988022100001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorSeymen, Figen
dc.language.isoen
dc.relation.ispartofInternational Endodontic Journal
dc.relation.isversionof10.1111/iej.13928en_US
dc.relation.publicationcategoryMakale - Ulusal Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectBMP Signalingen_US
dc.subjectAmelogenesis Imperfectaen_US
dc.subjectBiomineralizationen_US
dc.subjectHomeostasisen_US
dc.subjectSoft Tissue Calcificationen_US
dc.subjectStem Cellen_US
dc.titleFAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome
dc.typeArticle

Dosyalar

Lisans paketi
Listeleniyor 1 - 1 / 1
[ X ]
İsim:
license.txt
Boyut:
1.44 KB
Biçim:
Item-specific license agreed upon to submission
Açıklama:
İndir

Koleksiyon

PubMed İndeksli Yayınlar Koleksiyonu
Diş Hekimliği Fakültesi Yayın Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu
WoS İndeksli Yayınlar Koleksiyonu