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. FAM20A belongs to a family of 3 genes (FAM20A, FAM20B, and FAM20C) that encode kinases (phosphorylating enzymes) that modify proteins within the secretory pathway. FAM20C phosphorylates secretory calcium-binding phosphoproteins (SCPPs) that are critical for bone, dentin, and enamel biomineralization, and other calcium-binding proteins in milk and saliva. The function of FAM20A is unknown, but defects in the FAM20A gene have recently been shown to cause dental enamel defects along with enlarged gingiva (amelogenesis imperfecta and gingival fibromatosis syndrome or AIGFS; OMIM #614253). We identified three families with disease-causing mutations in FAM20A. All of the symptoms of AIGFS are also found in enamel-renal syndrome (ERS, OMIM #204690), which in addition features kidney calcifications known as nephrocalcinosis. We were only able to acquire a kidney ultrasound from one of our patients with FAM20A mutations, and it showed these kidney calcifications. We conclude that FAM20A mutations cause ERS and that persons diagnosed with AIGFS should have their kidneys examined. We also were able to obtain teeth from a patient with defined FAM20A mutations and to characterize the unusual mineral deposits that replace and add to normal tooth structures and may provide clues to the function of FAM20A.