Defining a New Candidate Gene for Amelogenesis Imperfecta: From Molecular Genetics to Biochemistry

Urzúa, Blanca; Ortega-Pinto, Ana; Morales-Bozo, Irene; Alcayaga, Gonzalo Rojas; Cifuentes, Víctor

doi:10.1007/s10528-010-9392-6

Cited by 46 publications

(42 citation statements)

References 72 publications

(117 reference statements)

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“…In humans, the hypomineralization or hypoplastic classes of amelogenesis imperfecta have been related to mutations in the following genes: AMELX (Hart et al 2002;Kim et al 2004;Stephanopoulos et al 2005;Urzúa et al 2011), ENAM (Hart et al 2003;Hu and Yamakoshi 2003;Kim et al 2005;Stephanopoulos et al 2005), and recently AMBN (Poulter et al 2014). The mouse model in which exons 5 and 6 are deleted from Ambn showed severe hypoplastic amelogenesis imperfecta that had no enamel formation on the tooth surface (Fukumoto et al the genuine casein kinase phosphorylating secretory calcium-binding phosphoproteins (Ishikawa et al 2012;Tagliabracci et al 2012).…”

Section: Introductionmentioning

confidence: 99%

The Importance of Serine Phosphorylation of Ameloblastin on Enamel Formation

et al. 2016

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FAM20C is a newly identified kinase on the secretory pathway responsible for the phosphorylation of serine residues in the Ser-x-Glu/pSer motifs in several enamel matrix proteins. Fam20C-knockout mice showed severe enamel defects very similar to those in the ameloblastin ( Ambn)–knockout mice, implying that phosphoserines may have a critical role in AMBN function. To test this hypothesis, we generated amelogenin ( Amel) promoter-driven Ambn-transgenic mice, in which Ser48, Ser226, and Ser227 were replaced by aspartic acid (designated as D-Tg) or alanines (designated as A-Tg). The negative charge of aspartic acid is believed to be able to mimic the phosphorylation state of serine, while alanine is a commonly used residue to substitute serine due to their similar structure. Using Western immunoblotting and quantitative polymerase chain reaction, the authors identified transgenic lines expressing transgenes somewhat higher (Tg+) or much higher (Tg++) than endogenous Ambn. The lower incisors collected from 7-d-old and 7-wk-old mice were analyzed by histology, scanning electron microscopy, immunohistochemistry, and Western immunoblotting to examine the morphology and microstructure changes in enamel, as well as the expression pattern of enamel matrix proteins. The A-Tg+ and A-Tg++ mice displayed severe enamel defects in spite of the expression level of transgenes, while the D-Tg+ and D-Tg++ mice showed minor to mild enamel defects, indicating that the D-Tg transgenes disturbed enamel formation less than the A-Tg transgenes did. Our results suggest that the phosphorylation state of serines is likely an essential component for the integrity of AMBN function.

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Section: Introductionmentioning

confidence: 99%

The Importance of Serine Phosphorylation of Ameloblastin on Enamel Formation

et al. 2016

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“…Prediction tools indicated that the target genes of miR-224 include genes encoding a set of crucial ion transporters required for the development of normal enamel, including SLC4A4 and CFTR (5,6,41). NBCe1 (encoded by SLC4A4), AE2 (encoded by SLC4A2), and CFTR (encoded by CFTR) have been proposed to compose a buffering system during ameloblast differentiation and enamel mineralization (5,6).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization

Fan

Zhou

et al. 2015

Molecular and Cellular Biology

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Enamel mineralization is accompanied by the release of protons into the extracellular matrix, which is buffered to regulate the pH value in the local microenvironment. The present study aimed to investigate the role of microRNA 224 (miR-224) as a regulator of SLC4A4 and CFTR, encoding the key buffering ion transporters, in modulating enamel mineralization. miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR. Overexpression of miR-224 downregulated SLC4A4 and CFTR expression in cultured human epithelial cells. A microRNA luciferase assay confirmed the specific binding of miR-224 to the 3= untranslated regions (UTRs) of SLC4A4 and CFTR mRNAs, thereby inhibiting protein translation. miR-224 agomir injection in mouse neonatal incisors resulted in normal enamel length and thickness, but with disturbed organization of the prism structure and deficient crystal growth. Moreover, the enamel Ca/P ratio and microhardness were markedly reduced after miR-224 agomir administration. These results demonstrate that miR-224 plays a pivotal role in fine tuning enamel mineralization by modulating SLC4A4 and CFTR to maintain pH homeostasis and support enamel mineralization.

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“…: amelogenin (AMELX), enamelin (ENAM), kallikrein-4 (KLK-4), matrix metalloprotease-20 (MMP-20), ameloblastin 3 and more recently DLX3, 4 FAM83H, 5,6,7 WDR72 5 and SLC4A4. 8 AMELX encodes a member of the amelogenin family of extracellular matrix protein and has an important role in biomineralization during tooth enamel development. 9 The X-linked amelogenin gene is located on the Xp22.31-…”

Section: 2mentioning

confidence: 99%

Amelogenin gene influence on enamel defects of cleft lip and palate patients

et al. 2014

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The aim of this study was to investigate the occurrence of mutations in the amelogenin gene (AMELX) in patients with cleft lip and palate (CLP) and enamel defects (ED). A total of 165 patients were divided into four groups: with CLP and ED (n=46), with CLP and without ED (n = 34), without CLP and with ED (n = 34), and without CLP or ED (n = 51). Genomic DNA was extracted from saliva followed by conducting a Polymerase Chain Reaction and direct DNA sequencing of exons 2 through 7 of AMELX. Mutations were found in 30% (n = 14), 35% (n = 12), 11% (n = 4) and 13% (n = 7) of the subjects from groups 1, 2, 3 and 4, respectively. Thirty seven mutations were detected and distributed throughout exons 2 (1 mutation -2.7%), 6 (30 mutations -81.08%) and 7 (6 mutations -16.22%) of AMELX. No mutations were found in exons 3, 4 or 5. Of the 30 mutations found in exon 6, 43.34% (n = 13), 23.33% (n = 7), 13.33% (n = 4) and 20% (n = 6) were found in groups 1, 2, 3 and 4, respectively. c.261 C > T (rs2106416), a silent mutation, was detected in 26 subjects, and found more significantly (p = 0.003) in patients with CLP (groups 1 and 2 -23.75%), compared with those without CLP (groups 3 and 4 -8.23%). In the groups without ED, this silent mutation was also found more significantly (p = 0.032) among subjects with CLP (17.65% in group 2), compared with those without CLP (7.8% in group 4). In conclusion, this study suggested that AMELX may be a candidate gene for cleft lip and palate.

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Defining a New Candidate Gene for Amelogenesis Imperfecta: From Molecular Genetics to Biochemistry

Cited by 46 publications

References 72 publications

The Importance of Serine Phosphorylation of Ameloblastin on Enamel Formation

The Importance of Serine Phosphorylation of Ameloblastin on Enamel Formation

MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization

Amelogenin gene influence on enamel defects of cleft lip and palate patients

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