FAM20A mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome
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Tarih
2023
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Aim: 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.
Açıklama
Anahtar Kelimeler
BMP Signaling, Amelogenesis Imperfecta, Biomineralization, Homeostasis, Soft Tissue Calcification, Stem Cell
Kaynak
International Endodontic Journal
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
56
Sayı
8
Künye
Wang, 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.
