FAM20A Mutations Associated with Enamel Renal Syndrome

Abstract

We identified two families with an autosomal-recessive disorder manifested by severe enamel hypoplasia, delayed and failed tooth eruption, misshapen teeth, intrapulpal calcifications, and localized gingival hyperplasia. Genetic analyses identified novel FAM20A mutations associated with the disease phenotype in both families. The proband of Family 1 had an altered splice junction in Intron 1 (g.502011G>C; c.405-1G>C) and a missense mutation in Exon 8 (g.65094G>A; c.1207G>A; p.D403N). The missense mutation is notable because D403 is strictly conserved among FAM20A homologues, and the corresponding defect in FAM20C caused osteosclerotic bone dysplasia and a loss of kinase activity. The proband at age 12 yrs tested negative for nephrocalcinosis. The proband and her affected father in Family 2 were homozygous for a single nucleotide deletion that altered a splice junction in Intron 10 (g.66622del; c.1361+4del). Minigene analyses demonstrated that this alteration precluded normal splicing. Immunohistochemistry (IHC) of mouse maxillary first molars localized FAM20A in secretory-stage ameloblasts, in odontoblasts, and in the eruption pathway. IHC of kidneys localized FAM20A in the renal tubules. We conclude that FAM20A is likely a secretory pathway kinase and that loss-of-function mutations cause pathology where its phosphorylations are necessary for normal development or homeostasis.

Nephrocalcinosis in Amelogenesis Imperfecta Caused by the <b><i>FAM20A</i></b> Mutation

“…This supports the notion that biominerilization is a tightly regulated process that has its promoters and inhibitors [41]. FAM20A seems to be one such inhibitor of ectopic calcification, and it has been found to be present in the kidneys by immunohistochemistry [19, 41]. In FAM20A knock-out mice, ectopic calcification was discovered in lungs and arteries throughout the body.…”

“…In FAM20A knock-out mice, ectopic calcification was discovered in lungs and arteries throughout the body. Two thirds of these mice had small, extensively calcified kidneys with pitted surfaces, and arteries within the kidney were calcified to a greater extent than the rest of the body [19, 41]. In a similar vein, Wang et al [19] have hypothesized that the absence of FAM20A may preclude the phosphorylation of proteins that normally inhibit calcification in the kidneys.…”

“…Two thirds of these mice had small, extensively calcified kidneys with pitted surfaces, and arteries within the kidney were calcified to a greater extent than the rest of the body [19, 41]. In a similar vein, Wang et al [19] have hypothesized that the absence of FAM20A may preclude the phosphorylation of proteins that normally inhibit calcification in the kidneys. The exact pathogenesis of nephrocalcinosis in patients with FAM20A mutations still remains to be elucidated, but FAM20A seems to inhibit ectopic calcification.…”

“…AIGFS and ERS share oral phenotypes; therefore, it is speculated that these diseases are related to each other or caused by a shared component in pathogenesis. Genetic studies of ERS families have identified mutations in FAM20A recently [19-21]; therefore, ERS and AIGFS are both associated with mutations in FAM20A [22]. …”

Oral manifestations in chronic uremia patients

“…23 The amount of enamel is substantially reduced and can even be absent in both the primary and permanent teeth. 24 In the pulp chambers, pulp stones can be observed in both the primary and secondary dentitions. Renal exams reveal nephrocalcinosis that is asymptomatic in children who are affected by ERS.…”