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PubMed2000

Unique enamel phenotype associated with amelogenin gene (AMELX) codon 41 point mutation.

Different mutations in the amelogenin gene (AMELX) result in the markedly different enamel phenotypes that are collectively known as amelogenesis imperfecta (AI). We hypothesize that unique phenotypes result from specific genetic mutations. The purpose of this study was to characterize the enamel compositional and structural features associated with a specific AMELX mutation in three families with X-linked AI. We performed mutational analysis by amplifying AMELX exons and sequencing the products. Permanent and primary affected (N = 6) and normal (N = 3) teeth were collected and examined by light, scanning, and transmission electron microscopy. Enamel proteins were evaluated by immunolocalization of amelogenin and amino acid analysis. AI-affected individuals all shared a common AMELX point mutation (C to A change at codon 41). The dental phenotypic findings were remarkably consistent in all affected individuals. The AI enamel was opaque, with numerous prism defects or holes encompassing the entire prism width. Affected crystallites appeared more radiolucent and morphologically less uniform, compared with that of normal enamel. Immunogold labeling with anti-amelogenin antibodies localized amelogenin to the crystallites but not to the inter-crystalline spaces. No immunogold labeling was seen in normal enamel. There was an increased and amelogenin-like protein content in AI enamel (0.95%) compared with normal enamel (0.13%). We conclude that this codon 41 C to A missense point mutation, in a highly conserved region of the AMELX gene, results in a remarkably consistent phenotype.

Amelogenesis Imperfecta↗
PubMed2006

Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG.

OBJECTIVE: The main clinical manifestations of amelogenesis imperfecta (AI) include alteration in the quality and quantity of enamel. AI is associated with different mutations in four genes: enamelin (ENAM), amelogenin (AMGX), kallikrein (KLK4) and enamelysin (MMP-20). Seven different mutations have been identified in the enamelin gene (ENAM). DESIGN: In this paper, we describe the phenotype and ultrastructure of enamel observed using scanning electron microscopy (SEM) in patients with two autosomal dominant (AD) mutations in the ENAM gene: g.13185-13186insAG and g.8344delG, each in one of two unrelated families. Mutations were confirmed by sequence analysis of PCR amplified products of all 10 exons and exon/intron boundaries of the ENAM gene. RESULTS: Phenotypic diversity was observed in patients with ENAM gene mutations g.13185-13186insAG with consecutive protein alteration designated as p.P422fsX488 within family 1. In the proband, the enamel of his entire dentition was chalky white with only mild local hypoplastic alteration, while the phenotypic appearance of his father's dentition was that of local hypoplastic AI. In patients with the ENAM gene mutation g.8344delG from family 2 with consecutive protein alteration designated as p.N197fsX277, generalised hypoplastic AI was observed. CONCLUSIONS: Ultrastructural enamel changes in the patient with the autosomal dominant ENAM g.13185-13186insAG mutation, described for the first time in this study, were less pronounced compared to ultrastructural changes in patients with the autosomal dominant ENAM mutation 8344delG. Ultrastructural characteristics of the g.13185-13186insAG mutation revealed deformed prisms, an oval shape on the cross-section and wider interprism spaces, while enamel with the ENAM mutation 8344delG was laminated, but prismless.

Amelogenesis Imperfecta↗
PubMed2000

Self-assembly properties of recombinant engineered amelogenin proteins analyzed by dynamic light scattering and atomic force microscopy.

Dynamic light scattering (DLS) analysis together with atomic force microscopy (AFM) imaging was applied to investigate the supramolecular self-assembly properties of a series of recombinant amelogenins. The overall objective was to ascertain the contribution of certain structural motifs in amelogenin to protein-protein interactions during the self-assembly process. Mouse amelogenins lacking either amino- or carboxy-terminal domains believed to be involved in self-assembly and amelogenins having single or double amino acid mutations identical to those found in cases of amelogenesis imperfecta were analyzed. The polyhistidine-containingfull-length recombinant amelogenin protein [rp(H)M180] generated nanospheres with monodisperse size distribution (hydrodynamic radius of 20.7 +/- 2.9 nm estimated from DLS and 16.1 +/- 3.4 nm estimated from AFM images), comparable to nanospheres formed by full-length amelogenin rM179 without the polyhistidine domain, indicating that this histidine modification did not interfere with the self-assembly process. Deletion of the N-terminal self-assembly domain from amelogenin and their substitution by a FLAG epitope ("A"-domain deletion) resulted in the formation of assemblies with a heterogeneous size distribution with the hydrodynamic radii of particles ranging from 3 to 38 nm. A time-dependent dynamic light scattering analysis of amelogenin molecules lacking amino acids 157 through 173 and containing a hemagglutinin epitope ("B"-domain deletion) resulted in the formation of particles (21.5 +/- 6.8 nm) that fused to form larger particles of 49.3 +/- 4.3 nm within an hour. Single and double point mutations in the N-terminal region resulted in the formation of larger and more heterogeneous nanospheres. The above data suggest that while the N-terminal A-domain is involved in the molecular interactions for the formation of nanospheres, the carboxy-terminal B-domain contributes to the stability and homogeneity of the nanospheres, preventing their fusion to larger assemblies. These in vitro findings support the notion that the proteolytic cleavage of amelogenin at amino- and carboxy-terminii occurring during enamel formation influences amelogenin to amelogenin interactions during self-assembly and hence alters the structural organization of the developing enamel extracellular matrix, thus affecting enamel biomineralization.

Amelogenesis Imperfecta↗
PubMed1975

Congenital oral anomalies in argentinian children.

A total of 6,180 Argentinian school-age children were examined clinically for the presence of oral congenital anomalies. The following prevalence figures were found: commissured lip pits (0.7%), ankyloglossia (0.1%), geographic tongue (1.5%), localized enamel hypomaturation (2.8%), median rhomboid glossitis (0.10/00), torus palatinus (0.30/00) and dentinogenesis imperfecta (0.30/00). Data are presented for the first time on snowcap amelogenesis imperfecta with a prevalence value of 0.1%.

Adolescent↗
PubMed2000

The enamel protein amelogenin binds to the N-acetyl-D-glucosamine-mimicking peptide motif of cytokeratins.

Amelogenins bind to GlcNAc of the dentine-enamel matrix proteins (Ravindranath, R. M. H., Moradian-Oldak, J., Fincham, A. G. (1999) J. Biol. Chem. 274, 2464-2471). The hypothesis that amelogenins may interact with the peptides that mimic GlcNAc is tested. GlcNAc-mimicking peptide (SFGSGFGGGY) but not its variants with single amino acid substitution at serine, tyrosine, or phenylalanine residues inhibited hemagglutination of amelogenins and the terminal tyrosine-rich amelogenin polypeptide (TRAP). The binding affinity of SFGSGFGGGY to amelogenins was confirmed by dosimetric binding of amelogenins or TRAP with [(3)H]peptide, specific binding in varying concentrations of the peptide, Scatchard plot analysis, and competitive inhibition with the unlabeled peptide. The ability of the peptide or GlcNAc to stoichiometrically inhibit TRAP binding of [(14)C]GlcNAc or [(3)H]peptide indicated that both the peptide and GlcNAc compete for a single binding site. Using different fragments of amelogenins, we have identified the peptide-binding motif in amelogenin to be the same as the GlcNAc-binding "amelogenin trityrosyl motif peptide." The GlcNAc-mimicking peptide failed to bind to the amelogenin trityrosyl motif peptide when the tyrosyl residues were substituted with phenylalanine or when the third proline was replaced with threonine, as in some cases of human X-linked amelogenesis imperfecta. This study documents that molecular mimicry may play a role in stability and organization of amelogenin during amelogenesis.

Acetylglucosamine↗
PubMed1998

[Hereditary diseases with tooth anomalies and their causal genes].

In this review, we describe the current knowledge and the advances in research on human genes whose defect leads to dental anomalies. Recently, it was demonstrated that a missense mutation of a human homeobox MSX1 gene causes autosomal dominant agenesis of second premolars and third molars. X-linked anhidrotic ectodermal dysplasia (EDA), characterized by abnormal hair, teeth, and sweat glands, was demonstrated to be caused by a mutation in a novel transmembrane protein gene that is expressed in epithelial cells and in other adult and fetal tissues. The autosomal dominant Rieger syndrome (RS) manifests hypodontia, adontia, iridogoniodysgenesis and umbilical anomalies. Recently, a novel homeobox gene, RIEG, of Otx family was cloned as a causal gene of RS. The several mutations have been reported on the genes causing hypophosphatasia, which is characterized by defective mineralization of the skeletal and dental structures. An autosomal dominant dentinogenesis imperfecta (DI) is mostly associated with osteogenesis imperfecta (OI). Most patients with DI have mutations in either the COL1A1 or COL1A2 genes of type I collagen. Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders characterized by a variety of developmental enamel defects including hypoplasia and hypomineralization, some of which have been revealed to be associated with defective amelogenin genes.

Alkaline Phosphatase↗
PubMed2005

Amelotin--a Novel Secreted, Ameloblast-specific Protein.

We aimed to analyze the differential gene expression in various murine dental tissues, expecting to find novel factors that are involved in tooth formation. We here describe the identification of a novel ameloblast-specific gene, amelotin (AMTN), by differential display polymerase chain-reaction (DD-PCR) analysis of microdissected ameloblasts, odontoblasts, dental pulp, and alveolar bone cells of 10-day-old mouse incisors. The conceptually translated protein sequence was unique and showed significant homology only with its human orthologue. The amelotin genes from mouse and human displayed a similar exon-intron structure and were expressed from loci on chromosomes 5 and 4, respectively, which have been associated with various forms of amelogenesis imperfecta. Expression of amelotin mRNA was restricted to maturation-stage ameloblasts in developing murine molars and incisors. Amelotin protein was efficiently secreted from transfected cells in culture. Taken together, our findings suggest that amelotin is a novel factor produced by ameloblasts that plays a critical role in the formation of dental enamel.

Alveolar Process↗
PubMed2001

Amelogenin-cytokeratin 14 interaction in ameloblasts during enamel formation.

The enamel protein amelogenin binds to the GlcNAc-mimicking peptide (GMp) (Ravindranath, R. M. H., Tam, W., Nguyen, P., and Fincham, A. G. (2000) J. Biol. Chem. 275, 39654-39661). The GMp motif is found in the N-terminal region of CK14, a differentiation marker for ameloblasts. The binding affinity of CK14 and amelogenin was confirmed by dosimetric binding of CK14 to recombinant amelogenin (rM179), and to the tyrosine-rich amelogenin polypeptide. The specific binding site for CK14 was identified in the amelogenin trityrosyl motif peptide (ATMP) of tyrosine-rich amelogenin polypeptide and specific interaction between CK14 and [(3)H]ATMP was confirmed by Scatchard analysis. Blocking rM179 with GlcNAc, GMp, or CK14 with ATMP abrogates the CK14-amelogenin interaction. CK14 failed to bind to ATMP when the third proline was substituted with threonine, as in some cases of human X-linked amelogenesis imperfecta or when tyrosyl residues were substituted with phenylalanine. Morphometry of developing teeth distinguished three phases of enamel formation; growth initiation phase (days 0-1), prolific growth phase (days 1-7), and growth cessation phase (post-day 7). Confocal microscopy revealed co-assembly of CK14/amelogenin in the perinuclear region of ameloblasts on day 0, migration of the co-assembled CK14/amelogenin to the apical region of the ameloblasts from day 1, reaching a peak on days 3-5, and a collapse of the co-assembly. Autoradiography with [(3)H]ATMP and [(3)H]GMp corroborated the dissociation of the co-assembly at the ameloblast Tomes' process. It is proposed that CK14 play a chaperon role for nascent amelogenin polypeptide during amelogenesis.

Acetylglucosaminidase↗
PubMed1989

Crystal morphology and decalcification patterns compared in rat and human enamel and synthetic hydroxyapatite.

The purpose of this investigation was to compare morphology and dissolution patterns by ultrastructural examination of rat and human enamel crystals as well as synthetic apatite crystals. Mature enamel crystals were of particular interest, since crystal maturation appears to be inhibited in amelogenesis imperfecta. Specimens were isolated from developing and mature rat incisor enamel. Rat enamel, mature human enamel, and synthetic apatite were thin-sectioned without decalcification and examined by transmission electron microscopy. Some sections were exposed to acid, and selected synthetic apatite sections were further treated for removal of embedding plastic, followed by vacuum-shadow-coating with carbon. Results showed that cross-sections of rat, human, and synthetic crystals had a distortion in the flattened hexagonal outline in regions where the growth of one crystal impinged on another. Crystal dissolution occurred preferentially along the c-axis, producing a central defect or hole in the crystals. Preliminary studies with weak acid on mature human enamel indicate that the relatively soluble crystal core is quickly dissolved, while the outer shell remains intact over a much longer period of time. In the mature rat and human enamel, this crystal hole formation had a consistent dimension of approximately 10-nm thickness. The crystal hole dimension was the same size as crystals that are formed during the early secretory phase in rat amelogenesis. Acid-treated synthetic apatite also showed dissolution of the crystal core along the c-axis, but dimensions of the hole were not consistent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Human developing enamel proteins exhibit a sex-linked dimorphism.

The amelogenin protein of developing dental enamel is generally accepted to mediate the regulation of the form and size of the hydroxyapatite crystallites during enamel biomineralization (1). A genetic disorder of enamel development (amelogenesis imperfecta) has been linked to the amelogenin gene AMEL(2-3), and loci regulating enamel thickness and tooth size have been mapped to the human sex chromosomes (4). In the human genome there are two AMEL loci with one copy of the gene on each of the sex chromosomes (AMELX and AMELY), whereas in the mouse only an AMELX locus is present (5). It is presently unknown if human AMELY is transcriptionally active. These observations prompted us to examine specimens of human developing enamel for sexual dimorphism at the protein level. We report here, for the first time, a diagnosis of differences in human enamel proteins which permits the distinction of specimens according to the sex of the individual.

Ameloblasts↗
PubMed2006

A developmental comparison of matrix metalloproteinase-20 and amelogenin null mouse enamel.

Mutations in both the human amelogenin and human matrix metalloproteinase-20 (MMP20, enamelysin) genes cause amelogenesis imperfecta. Both genes have also been individually deleted from the mouse and each deletion results in defective dental enamel. Here, we compare the stage-specific progression of enamel development in continuously erupting mouse incisors from amelogenin null and MMP-20 null mice. Our goal was to closely examine differences in enamel and enamel organ structure between these mice that would allow a better understanding of each protein's function. The predominant feature of the amelogenin null incisors was the late onset of mineral deposition, with little or no protein present within the forming mineral. Conversely, the developing MMP-20 null incisors had a layer of protein between the apical surface of the ameloblasts and the forming enamel. Furthermore, the protein present within the enamel matrix was disorganized. An analysis of crystal structure demonstrated that the thin amelogenin null enamel was plate-like, while the MMP-20 null enamel had a disrupted prism pattern. These results suggest that amelogenin is essential for appositional crystal growth during the early to mid-secretory stage and for the maintenance of the crystal ribbon structure. They also suggest that MMP-20 is responsible for enamel matrix organization and for subsequent efficient reabsorption of enamel matrix proteins. Both genes are essential for the generation of full-thickness enamel containing the characteristic decussating prism pattern.

Absorption↗
PubMed2002

Linear and whorled nevoid hypermelanosis with bilateral giant cerebral aneurysms.

A 24-year-old woman presented with bilateral giant intracavernous carotid artery aneurysms manifesting as a cavernous sinus syndrome on the left side, and anisocoria, ophthalmic pain, and oculomotor paresis on the left side. Physical examination showed mild hyperextensibility of the metacarpophalangeal joints, amelogenesis imperfecta, and hyperpigmentation following Blaschko lines. Analysis of the NEMO gene for incontinentia pigmenti syndrome and of collagen III for Ehlers-Danlos type IV was normal. Skewed X-inactivation patterns in blood lymphocytes were detected. To the best of our knowledge, this association of linear hyperpigmentation and cerebral aneurysms has never been previously reported.

Adult↗
PubMed1988

Molecular determinants of cranial neural crest-derived odontogenic ectomesenchyme during dentinogenesis.

Positional information on tooth morphogenesis is investigated by the identification of when and where phenotypic markers are expressed during odontogenesis. This temporal and positional information is correlated with the instructive and permissive signaling required for both dentinogenesis and amelogenesis. Of particular interest is the establishment of a map for the cranial neural crest-derived dental papilla ectomesenchyme and the odontoblast cell lineages. The expression of ectomesenchyme-derived cytotactin, dentin phosphoprotein, and epithelial-derived enamel proteins was studied in mice using embryonic, fetal, and postnatal mandibular first molar tooth organ development. This review summarizes the observations in the context of instructive epithelial-mesenchymal interactions and suggests that amelogenesis imperfecta and dentinogenesis imperfecta may in part be explained by alterations in these differentiation markers. Recombinant DNA methods should facilitate future investigations of these inherited dental disorders.

Animals↗
PubMed2006

A newly recognized autosomal recessive syndrome with short stature and oculo-skeletal involvement.

This report describes a young girl and her cousin presenting with postnatal short stature, strabismus, photophobia, retinitis pigmentosa, short neck, rhizomelic shortening of the long bones, short and slightly bowed humeri with prominent deltoid tuberosities, short and wide ribs and clavicles, dorso-lumbar scoliosis, biconcave vertebral bodies of the thoraco-lumbar spine, and narrowed lumbar canal. In addition, in the girl there were amelogenesis imperfecta of the hypomaturation type, and the radiographs showed short distal ulnae, sloping epiphyses of the radii, short femoral necks, and slightly flat uncovered femoral heads. The children's parents are first cousins. Differential diagnoses are discussed and the possibility of a newly recognized oculo-skeletal syndrome is raised.

Abnormalities, Multiple↗
PubMed2005

Molecular evolution of amelogenin in mammals.

An evolutionary analysis of mammalian amelogenin, the major protein of forming enamel, was conducted by comparison of 26 sequences (including 14 new ones) representative of the main mammalian lineages. Amelogenin shows highly conserved residues in the hydrophilic N- and C-terminal regions. The central hydrophobic region (most of exon 6) is more variable, but it has conserved a high amount of proline and glutamine located in triplets, PXQ, indicating that these residues play an important role. This region evolves more rapidly, and is less constrained, than the other well-conserved regions, which are subjected to strong constraints. The comparison of the substitution rates in relation to the CpG richness confirmed that the highly conserved regions are subjected to strong selective pressures. The amino acids located at important sites and the residues known to lead to amelogenesis imperfecta when substituted were present in all sequences examined. Evolutionary analysis of the variable region of exon 6 points to a particular zone, rich in either amino acid insertion or deletion. We consider this region a hot spot of mutation for the mammalian amelogenin. In this region, numerous triplet repeats (PXQ) have been inserted recently and independently in five lineages, while most of the hydrophobic exon 6 region probably had its origin in several rounds of triplet insertions, early in vertebrate evolution. The putative ancestral DNA sequence of the mammalian amelogenin was calculated using a maximum likelihood approach. The putative ancestral protein was composed of 177 residues. It already contained all important amino acid positions known to date, its hydrophobic variable region was rich in proline and glutamine, and it contained triplet repeats PXQ as in the modern sequences.

Amelogenin↗
PubMed1989

The polarized light microscopy and ultrastructure of Polynesian pigmented tooth enamel.

Transmitted and polarized light microscopy of unerupted and erupted teeth affected by a pigmented anomaly found in two geographically isolated Polynesian populations, the New Zealand Maori and the French Polynesian Marquesas Islander, showed similar histological characteristics. Mounted in water, the pigmented areas were positively birefringent and covered with a thin negatively birefringent surface layer 200-250 microns thick. Cervical areas were negatively birefringent. Transmission electron microscopy of argon-ion-beam thinned specimens of affected enamel revealed large voids, disruption in the packing of crystals and spacing at prism boundaries. In the surface layer of enamel from erupted and unerupted teeth, the intra- and interprismatic spaces were occluded by fine crystals or amorphous material. A well-defined prism structure and close crystal packing were found in cervical enamel. The ultrastructure of these pigmented enamels was similar to and consistent with a hypomaturation type of amelogenesis imperfecta.

Birefringence↗
PubMed1975

Oral manifestations of Morquio's syndrome.

The clinical and laboratory findings in two siblings affected with Morquio's syndrome are described. The oral findings, consisting of disturbances in the structure of the enamel in both deciduous and permanent teeth, resemble those of amelogenesis imperfecta, Type 1. Preformed crowns are recommended as the initial treatment, in order to avoid loss of vertical height. The dentist's familiarity with the oral manifestations of Morquio's disease may contribute to the early detection of this condition.

Child↗