FAM20A mutations cause both AIGFS and ERS [17–23]. Fam20a−/− mice present with the dental phenotype observed in patients with FAM20A mutations, i.e., enamel defects, microdontia and flat molars. The common phenotype observed in mouse and man suggests that FAM20A plays a role in enamel secretion and maturation stages, although its distinct roles in amelogenesis and nephrocalcinosis remain to be discovered. The FAM20 family includes FAM20A, FAM20B and FAM20C proteins. FAM20C is phylogenetically closer to FAM20A than FAM20B and has been more extensively studied.
FAM20C is a Golgi casein kinase that phosphorylates several secreted proteins implicated in biomineralization, including the SIBLING proteins (small integrin-binding ligand, N-linked glycoproteins) . It is expressed by osteoblasts, ameloblasts (during secretion stage) and odontoblasts and plays an essential role in tooth development [18, 20, 21]. Mutations of FAM20C cause autosomal-recessive neonatal osteosclerotic bone dysplasia (Raine syndrome; OMIM 259775). FAM20B is less well understood and is not currently associated with human disease. Fam20b deletion in a mouse model is embryonically lethal. Embryos at E12.5 show severely stunted growth, with multisystem organ hypoplasia and delayed development, most evident in the skeletal system, eyes, lung, gastro-intestinal tract and liver . Current understanding is that FAM20B is functionally important in cartilage matrix formation and skeletal development by controlling proteoglycan synthesis .
Based on the high sequence homology of FAM20 family members, it may be speculated that FAM20A is an additional kinase with specific targets implicated in mineralization and/or calcium transport and proteoglycan synthesis. While the reported clinical features of ERS/AIGFS primarily involve the orodental tissues and kidneys, FAM20A expression has been detected in additional tissues by RT-PCR: liver, lung, heart, stomach, placenta, parathyroid, thymus and kidney . Fam20a,b,c transcripts have been detected during odontogenesis at mouse E14.5 molar and incisor cap stages . In situ hybridization and immunolocalization performed in mouse mandibular incisors revealed Fam20a expression in all enamel organ cells (ameloblasts, stratum intermedium and stellate reticulum), odontoblasts, dental pulp cells and suprabasal gingival epithelium, with lower expression in the ameloblasts [20, 23].
Histological analysis of Fam20a−/− mouse incisors demonstrated that the ameloblast layer becomes progressively disorganized. All other examined tissues (bone, dentine, cementum) appeared normal. Interestingly, in line with the hamartoma phenotype reported in some human cases [33, 35], the enamel organ appeared disorganized, forming odontogenic tumor-like structures . A similar phenotype was described in Msx2−/− mice, raising the possibility that MSX2 and FAM20A function within a shared molecular pathway . Ectopic calcification was prominent in the kidneys of Fam20a−/− mice, but was also present in muscular arteries, lungs, heart, eyes, pancreas, thalamus, uterus, choroid plexus, skeletal muscle, and cutaneous tissue. Blood levels of calcium and phosphate were normal .