title: 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.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI, USA Oral Health Sciences Program, University of Michigan School of Dentistry, 1011 North University, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, 275-1 Yongon-dong, Chongno-gu, Seoul 110-768, Korea Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, USA jsimmer@umich.edu murimchoi@snu.ac.kr.
authors.forename: M
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Richardson
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Reid
authors.affiliation: Department of Pedodontics, Istanbul University, Faculty of Dentistry, Istanbul, Turkey.
authors.forename: F
authors.initials: F
authors.lastname: Seymen
authors.affiliation: Department of Pedodontics, Istanbul University, Faculty of Dentistry, Istanbul, Turkey.
authors.forename: M
authors.initials: M
authors.lastname: Yildirim
authors.affiliation: Department of Pedodontics, Istanbul University, Faculty of Dentistry, Istanbul, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Tuna
authors.affiliation: Department of Pedodontics, Istanbul University, Faculty of Dentistry, Istanbul, Turkey.
authors.forename: K
authors.initials: K
authors.lastname: Gençay
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI, USA jsimmer@umich.edu murimchoi@snu.ac.kr.
authors.forename: J P
authors.initials: JP
authors.lastname: Simmer
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Hu
mesh_terms: D000409:Alanine / Q000235:genetics; D000565:Ameloblasts / Q000502:physiology; D000566:Amelogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000502:physiology*; D001120:Arginine / Q000235:genetics; D020013:Calcium Signaling / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003545:Cysteine / Q000235:genetics; D003596:Cytosine; D003744:Dental Enamel Hypoplasia / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010375:Pedigree; D000071737:Stromal Interaction Molecule 1; D013941:Thymine; D014633:Valine / Q000235:genetics
chemical_list: D017920:Antiporters; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C470570:SLC24A4 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D003596:Cytosine; D001120:Arginine; D014633:Valine; D003545:Cysteine; D000409:Alanine; D013941:Thymine
keywords: amelogenesis imperfecta; calcium; inherited diseases; mutations; tooth