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FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many <jats:italic>FAM20A<\/jats:italic> pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease\u2010causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>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 <jats:italic>FAM20A<\/jats:italic> splice\u2010site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Biallelic <jats:italic>FAM20A<\/jats:italic> mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590\u20105T&gt;A, c.625T&gt;A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G&gt;A (p.Arg411Gln), c.1297A&gt;G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590\u20105T&gt;A splice\u2010site mutation caused Exon 3 skipping, which resulted in an in\u2010frame 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 <jats:italic>DSPP<\/jats:italic>, <jats:italic>MMP9<\/jats:italic>, <jats:italic>MMP20<\/jats:italic> and <jats:italic>WNT10A<\/jats:italic>. 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 <jats:italic>GDF7<\/jats:italic>, <jats:italic>GDF15<\/jats:italic>, <jats:italic>BMP3<\/jats:italic>, <jats:italic>BMP8A<\/jats:italic>, <jats:italic>BMP8B<\/jats:italic>, <jats:italic>BMP4<\/jats:italic> and <jats:italic>BMP6<\/jats:italic> were upregulated, while BMP antagonists <jats:italic>GREM1<\/jats:italic>, <jats:italic>BMPER<\/jats:italic> and <jats:italic>VWC2<\/jats:italic> showed decreased expression in ERS dental pulp tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Upregulation 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\u2010FAM20C kinase complex.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.13928","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T20:46:00Z","timestamp":1683751560000},"page":"943-954","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<i>FAM20A<\/i> mutations and transcriptome analyses of dental pulp tissues of enamel renal syndrome"],"prefix":"10.1111","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8378-5880","authenticated-orcid":false,"given":"Shih\u2010Kai","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"},{"name":"Department of Pediatric Dentistry National Taiwan University Children's Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin\u2010Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University School of Dentistry  Taipei City Taiwan"},{"name":"Department of Pediatric Dentistry National Taiwan University Children's Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung\u2010Ying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery National Taiwan University Hospital  Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Figen","family":"Seymen","sequence":"additional","affiliation":[{"name":"Department of Pedodontics, Faculty of Dentistry Altinbas University  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mine","family":"Koruyucu","sequence":"additional","affiliation":[{"name":"Department of Pedodontics, Faculty of Dentistry Istanbul University  Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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