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FAM20A mutations can cause enamel-renal syndrome (ERS).

ABSTRACT: Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis. Recently, mutations in FAM20A were reported to cause amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS), which closely resembles ERS except for the renal calcifications. We characterized three families with AIGFS and identified, in each case, recessive FAM20A mutations: family 1 (c.992G>A; g.63853G>A; p.Gly331Asp), family 2 (c.720-2A>G; g.62232A>G; p.Gln241_Arg271del), and family 3 (c.406C>T; g.50213C>T; p.Arg136* and c.1432C>T; g.68284C>T; p.Arg478*). Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to ERS. By characterizing teeth extracted from the family 3 proband, we demonstrated that FAM20A(-/-) molars lacked true enamel, showed extensive crown and root resorption, hypercementosis, and partial replacement of resorbed mineral with bone or coalesced mineral spheres. Supported by the observation of severe ectopic calcifications in the kidneys of Fam20a null mice, we conclude that FAM20A, which has a kinase homology domain and localizes to the Golgi, is a putative Golgi kinase that plays a significant role in the regulation of biomineralization processes, and that mutations in FAM20A cause both AIGFS and ERS.

SUBMITTER: Wang SK

PROVIDER: S-EPMC3585120 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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FAM20A mutations can cause enamel-renal syndrome (ERS).

Wang Shih-Kai SK Aref Parissa P Hu Yuanyuan Y Milkovich Rachel N RN Simmer James P JP El-Khateeb Mohammad M Daggag Hinda H Baqain Zaid H ZH Hu Jan C-C JC

PLoS genetics 20130228 2

Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis. Recently, mutations in FAM20A were reported to cause amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS), which closely resembles ERS except for the renal calcifications. We characterized three families with AIGFS and identified, in each case, recessive FAM20A mutations: family 1 (c.992G ...[more]

PMID: 23468644

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Project description:AimBiallelic 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 intrapulpal calcifications.MethodologyPhenotypic 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.ResultsBiallelic 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_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (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 overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling 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.ConclusionsUpregulation of BMP signalling 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.

Project description:BackgroundEnamel renal syndrome (ERS) (OMIM 204690) is a rare autosomal recessive disorder characterized by hypoplastic amelogenesis imperfecta, failed tooth eruption, intrapulpal calcifications, gingival enlargement, and nephrocalcinosis. The rarity of the condition and the variability of the phenotype has led to ERS not being fully characterized.ObjectiveThis scoping review aims to account for the range and current state of knowledge on ERS and synthesize these findings into a comprehensive summary, focusing on the pathophysiology, genotype-phenotype correlations, and patient management from a dental perspective.MethodsThe authors will conduct a systematic search of PubMed (MEDLINE), BioMed Central, EbscoHost Web, Web of Science, and WorldCat. We will include all studies with human participants with a confirmed diagnosis of ERS. Articles will be screened in two stages (ie, initially by title and abstract screening and then full-text screening by two independent reviewers). Data extraction will be conducted using a customized electronic data extraction form. We will provide a narrative synthesis of the findings from the included studies. We will structure the results according to themes.ResultsThis protocol is registered with the Open Science Framework. The electronic search was conducted in July 2020 and updated in April 2021. The research findings will be published in an open access journal.ConclusionsDentists should be able to identify patients with clinical features of ERS so that they receive appropriate referrals for renal evaluation, genetic counseling, and oral rehabilitation to increase the patient's quality of life. A scoping review is the most appropriate method to conduct this comprehensive exploration of the current evidence, which may be sparse due to the rarity of the condition. It will also enable us to identify gaps in the research.Trial registrationOpen Science Framework; https://osf.io/cghsa.International registered report identifier (irrid)DERR1-10.2196/29702.

Dataset Information

FAM20A mutations can cause enamel-renal syndrome (ERS).

Publications

FAM20A mutations can cause enamel-renal syndrome (ERS).

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