STIM1 and SLC24A4 Are Critical for Enamel Maturation

Abstract

Dental enamel formation depends upon the transcellular transport of Ca(2+) by ameloblasts, but little is known about the molecular mechanism, or even if the same process is operative during the secretory and maturation stages of amelogenesis. Identifying mutations in genes involved in Ca(2+) homeostasis that cause inherited enamel defects can provide insights into the molecular participants and potential mechanisms of Ca(2+) handling by ameloblasts. Stromal Interaction Molecule 1 (STIM1) is an ER transmembrane protein that activates membrane-specific Ca(2+) influx in response to the depletion of ER Ca(2+) stores. Solute carrier family 24, member 4 (SLC24A4), is a Na(+)/K(+)/Ca(2+) transporter that exchanges intracellular Ca(2+) and K(+) for extracellular Na(+). We identified a proband with syndromic hypomaturation enamel defects caused by a homozygous C to T transition (g.232598C>T c.1276C>T p.Arg426Cys) in STIM1, and a proband with isolated hypomaturation enamel defects caused by a homozygous C to T transition (g.124552C>T; c.437C>T; p.Ala146Val) in SLC24A4. Immunohistochemistry of developing mouse molars and incisors showed positive STIM1 and SLC24A4 signal specifically in maturation-stage ameloblasts. We conclude that enamel maturation is dependent upon STIM1 and SLC24A4 function, and that there are important differences in the Ca(2+) transcellular transport systems used by secretory- and maturation-stage ameloblasts.

Hypomaturation amelogenesis imperfecta caused by a novel SLC24A4 mutation

“…6). 16, 26, 33 The enamel phenotype of the proband closely matches those of previously reported AI-causing SLC24A4 defects.…”

“…18, 19 As enamel malformations are often the only clinical manifestation evident at the time of diagnosis, clinicians are frequently uncertain as to whether the presenting case is isolated or syndromic. Syndromic AI and their genetic causes include Cone-Rod Dystrophy and AI ( CNNM4 ), 20 Enamel Renal Syndrome ( FAM20A ), 21, 22 Tricho-Dento-Osseous syndrome ( DLX3 ), 23 Immunodeficiency 9 ( ORAI ), 24 Immunodeficiency 10 ( STIM1 ), 25, 26 Oculodentodigital Dysplasia ( GJA1 ), 27, 28 Kohlschütter–Tönz Syndrome ( ROGDI ), 29 and Nance Horan Syndrome (NHS). 11, 30 Although some syndromic AI diseases have distinctive clinical features, identifying the gene/mutation that causes the disease provides a specific diagnosis, discerns between isolated and syndromic AI, and improves assessment of the patients’ prognosis.…”

Store-operated Ca2+ entry controls ameloblast cell function and enamel development

“…protein involved in Ca 2+ extrusion expressed by ameloblasts, the exchanger NCKX4 (3,(17)(18)(19), was highly upregulated ( Figure 4A). In WT ameloblasts, NCKX4 is localized at the apical pole of ruffled-ended ameloblasts, thus serving as a key extrusion path for Ca 2+ ( Figure 4B).…”

Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation

“…2013) and is thought to secrete calcium into the maturation stage enamel matrix (Wang et al. 2014a). To assess if the hypomaturation defects in the enamel of Wdr72 −/− mice can be caused by impaired expression or localization of this calcium transporter, we compared the immunolocalizations of NCKX4 in D11 maxillary molars and in D14 mandibular incisor cross-sections (Fig 11.…”