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PubMed1989

Of mice and men: anatomy of the amelogenin gene.

Mammalian enamel matrix is composed of two principal proteins, the enamelins and amelogenin. Recombinant complementary DNA (cDNA) molecules for the predominant mouse amelogenin have been identified, characterized by direct determination of the DNA sequence, and used as a specific hybridization probe. The spatial- and temporal-restricted pattern for amelogenin gene expression within developing mouse molars has been traced at the level of a single cell using in situ hybridization. The mouse genome has been shown to contain only one copy of the amelogenin (AMEL) gene which is not amplified or rearranged during ameloblast determination. In contrast, the human genome contains two copies of the AMEL gene, one residing on the X chromosome and one upon the Y chromosome. These observations, the availability of specific enamel gene probes coupled with the application of new techniques in molecular biology now afford unique opportunities for the analysis of the molecular basis of inherited defects of human enamel such as amelogenesis imperfecta. Recent advances towards obtaining a physical map and the complete nucleotide sequence for the human genome, as well as the documented developmental biology, defined genetics and transgenic capability of the mouse, suggest that mouse and man are the most relevant and potentially informative models for analysis of normal and abnormal enamel biomineralization.

Amelogenesis Imperfecta↗

PubMed1998

Tuftelin--aspects of protein and gene structure.

The acidic enamel protein tuftelin has now been cDNA cloned, sequenced and characterized in a number of vertebrate species. Recently, the bovine tuftelin gene structure was elucidated. Cloning of the human tuftelin gene and partial sequencing of a number of exons have also been achieved. Immunologically, the protein has been shown to be conserved throughout 550 million years of vertebrate evolution. The gene has been localized to the long arm of the autosomal chromosome 1. The mapping of the human tuftelin gene to a well-defined cytogenetic region could be important in understanding the etiology of autosomally inherited amelogenesis imperfecta, the most common hereditary disease of enamel. The present paper reviews the primary structure, mRNA/cDNA structure, and gene structure of tuftelin. It describes its immunolocalization at the light microscope level and at the ultrastructural level in both the ameloblast cells and in the extracellular enamel matrix. The timing of tuftelin expression and its possible roles in enamel formation are discussed.

Ameloblasts↗

PubMed2001

Improving quality of life with a team approach: a case report.

An adolescent female who presented amelogenesis imperfecta with severe anterior open bite, long face, facial asymmetry, high angle, and Class III skeletal pattern was treated with an interdisciplinary (orthodontics, orthognathic surgery, and prosthodontics) treatment approach. Presurgical orthodontic treatment was followed by surgical maxillary posterior impaction with anterior advancement and mandibular setback operation with vertical chin reduction and genioplasty. After the surgery, anterior ceramic laminate veneers and posterior full ceramic onlay-crowns were performed. The results showed that function and esthetics were achieved successfully with interdisciplinary collaboration.

Adolescent↗

PubMedDate not supplied

[Kohlschütter syndrome--an example of a rare progressive neuroectodermal disease. Case report and review of the literature].

Kohlschütter's syndrome is a combination of amelogenesis imperfecta, progressive mental retardation and epileptic seizures. We report on a patient with typical signs of this syndrome. Beneath severe enamal defects of teeth, the patient has been suffering from progressive mental and motoric retardation from the age of six months. Although there is pathologic activity in EEG, seizures have not yet appeared. MRT shows distinct signs of cerebral atrophy. Apart from this patient 15 patients in 4 families have been reported up to now in literature. The article compares diagnostic results in this case with those reported in literature.

Amelogenesis Imperfecta↗

PubMed2006

Yellow teeth, seizures, and mental retardation: a less severe case of Kohlschütter-Tönz syndrome.

We describe an 11-year-old boy with hypoplastic amelogenesis imperfecta, yellow teeth, seizures, and developmental delay, which are the hallmarks of Kohlschütter-Tönz syndrome. Compared to other reported cases of the syndrome, our patient had less severe developmental delay. Also, spasticity and loss of mental capacity should not be considered obligatory manifestations of the syndrome because they are not present in half of reported patients, as well as in our family. Origin of the parents of our patient from neighboring villages supports autosomal recessive inheritance of Kohlschütter-Tönz syndrome.

Abnormalities, Multiple↗

PubMed1994

Ataxia, mental deterioration, epilepsy in a family with dominant enamel hypoplasia: a variant of Kohlschütter-Tönz syndrome?

We describe 3 sibs, their father, and paternal grandfather with amelogenesis imperfecta. In 2 sibs and the father the defect is associated with a neurological syndrome which has a wide range of phenotypic variability. The proposita has ataxia, EEG abnormalities, moderate dementia, and enamel hypoplasia. This case and the affected relatives are discussed in relation to Kohlschütter-Tönz syndrome and neuroectodermal diseases. The syndrome described here, characterized by the association of a genetic enamel defect and neurological impairment, may be of considerable interest in advancing genetic and clinical knowledge on ectodermal tissues and their development.

Abnormalities, Multiple↗

PubMed1993

Molecular basis and consequences of a deletion in the amelogenin gene, analyzed by capture PCR.

A mutation that disrupts the gene for one of the major proteins in tooth enamel has been investigated. The mutation is located in the amelogenin gene and causes X-linked amelogenesis imperfecta, characterized by defective mineralization of tooth enamel. We have isolated the breakpoints of a 5-kb deletion in the amelogenin gene on the basis of nucleotide sequence information located upstream of the lesion, using a technique termed capture PCR. The deletion removes five of the seven exons, spanning from the second intron to the last exon. Only the first two codons for the mature protein remain, consistent with the relatively severe phenotype of affected individuals in the present family. The mutation appears to have arisen as an illegitimate recombination event since of 11 nucleotide positions immediately surrounding the two breakpoints, 9 are identical.

Amelogenesis Imperfecta↗

PubMed2005

Tooth enamel defects in mice with a deletion at the Arhgap 6/Amel X locus.

The amelogenin proteins regulate enamel mineral formation in the developing tooth. The human AMELX gene, which encodes the amelogenin proteins, is located within an intron of the Arhgap 6 gene. ARHGAP 6 encodes a Rho GAP, which regulates activity of Rho A, a small G protein involved in intracellular signal transduction. Mice were generated in which the entire ARHGAP 6 gene was deleted by Cre-mediated recombination, which also removed the nested Amel X gene. Enamel from these mice appeared chalky white, and the molars showed excessive wear. The enamel layer was hypoplastic and non-prismatic, whereas other dental tissues had normal morphology. This phenotype is similar to that reported for Amel X null mice, which have a short deletion that removed the region surrounding the translation initiation site, and resembles some forms of X-linked amelogenesis imperfecta in humans. Analysis of the enamel from the Arhgap 6/Amel X-deleted mice verifies that the Amel X gene is nested within the murine Arhgap 6 gene and shows that removal of the entire Amel X gene leads to a phenotype similar to the earlier Amel X null mouse results, in which no amelogenin protein was detected. However, an unusual layer of aprismatic enamel covers the enamel surface, which may be related to the 1.1-Mb deletion, which included Arhgap 6 in these mice.

Amelogenesis Imperfecta↗

PubMed2001

Cloning and characterization of the mouse and human enamelin genes.

Enamelin is likely to be essential for proper dental enamel formation. It is secreted by ameloblasts throughout the secretory stage and can readily be isolated from the enamel matrix of developing teeth. The gene encoding human enamelin is located on the long arm of chromosome 4, in a region previously linked to an autosomal-dominant form of amelogenesis imperfecta (AI). To gain information on the structure of the enamelin gene and to facilitate the future assessment of the role of enamelin in normal and diseased enamel formation, we have cloned and characterized the mouse and human enamelin genes. Both genes are about 25 kilobases long. The enamelin gene has 10 exons interrupted by 9 introns. Translation initiates in exon 3 and terminates in exon 10. All of the intron/exon junctions within the mouse and human enamelin coding regions are between codons, so there are no partial codons in any exon, and deletion of one or more coding exons by alternative RNA splicing would not shift the downstream reading frame.

Ameloblasts↗

PubMed2005

Phenotype of ENAM mutations is dosage-dependent.

Five mutations in the ENAM gene have been found to cause hypoplastic amelogenesis imperfecta (AI), with phenotypes ranging from localized enamel pitting in carriers to severe hypoplastic AI. To determine the generality of ENAM mutations in hypoplastic AI, we sequenced the ENAM gene in ten Turkish families segregating autosomal hypoplastic AI. In two families, ENAM mutations were found. A novel nonsense mutation (g.12663C>A; p.S246X) was identified in one family segregating local hypoplastic AI as a dominant trait. Affected individuals in a second family segregating autosomal-recessive AI were compound heterozygotes for a novel insertion mutation (g.12946_12947insAGTCAGTACCAGTACTGTGTC) and a previously described insertion (g.13185_13186insAG) mutation. Heterozygous carriers of either insertion had a localized enamel-pitting phenotype. These findings substantiate that enamel phenotypes of ENAM mutations may be dose-dependent, with generalized hypoplastic AI segregating as a recessive trait and localized enamel pitting segregating as a dominant trait.

Adenine↗

PubMedDate not supplied

Clinical diagnosis and management strategies of amelogenesis imperfectavariants.

Amelogenesis imperfecta (AI) is a group of inherited disorders primarily affecting dental enamel. Variants of AI generally are classified as hypoplastic, hypocalcified, or hypomaturation types based on the primary enamel defect. The aim of this study was to analyze the clinical presentations, diagnostic features, and clinical complications of different variants of AI. Thirty-two patients from 17 families with several subtypes of AI were studied. The results showed that distinctive clinical features may be observed in each variant. However, all AI patients suffered common clinical problems of poor esthetics, teeth sensitivity, and loss of occlusal vertical dimension. The mildest problems were found in the pitted hypoplastic type whereas the most severe problems were encountered in the hypocalcified type of AI. Management strategies include composite resin veneers and jacket crowns for anterior teeth as well as steel crowns for posterior teeth. Knowledge of the clinical features and dental complications of each variant of AI helps in the diagnosis of the condition and allows institution of early preventive measures.

Adolescent↗

PubMed2003

Dental structural diseases mapping to human chromosome 4q21.

Genetic diseases affecting tooth structure have been classified by the tissue affected enamel versus dentin, and their pattern of inheritance autosomal dominant, autosomal recessive, or X-linked. Advances in molecular genetics and the Human Genome Project have provided substantial progress regarding the identification of genes involved in the pathogenesis of human diseases. These include dental diseases affecting enamel and dentin formation: amelogenesis imperfecta (AI), dentinogenesis imperfecta (DGI) types II and III, and dentin dysplasia (DD) type II. Linkage studies using large informative families have provided insight identifying two proximal gene clusters on human chromosome 4q21 that contain the critical loci for five dental structural diseases. Studies related to the autosomal dominant forms of AI, representing approximately 85% of all cases, have established linkage to 4q21 for two forms: local hypoplastic and smooth hypoplastic AI. Two enamel matrix proteins, ameloblastin and enamelin, have been mapped within the critical regions for these diseases. Located more toward the telomere is another cluster containing loci for three dentin diseases: DGI type II, type III, and DD type II. Located within an overlapping segment of these diseases is a dentin/bone gene cluster that contains osteopontin, bone sialoprotein, matrix extracellular phosphoglycoprotein also known as osteoblast/osteocyte factor 45 or osteoregulin, dentin matrix protein 1, and dentin sialophosphoprotein. Continuing molecular genetic studies will facilitate the identification of novel tooth matrix proteins within these two tooth matrix gene clusters as well as the identification of additional autosomal dominant AI loci.

Amelogenesis Imperfecta↗

PubMed1982

Aetiology of developmental enamel defects not related to fluorosis.

The aetiological factors in enamel defects of a non-fluoride nature can be divided into systemic and local. The systemic factors comprise a variety of conditions: genetically determined, chromosomal anomalies, congenital defects, inborn errors of metabolism, neonatal disturbances, infectious diseases, neurological disturbances, endocrinopathies, nutritional deficiencies, nephropathies, enteropathies, liver diseases and intoxications. The genetically determined enamel defects include amelogenesis imperfecta, which may occur as an isolated phenomenon or as part of other disorders such as epidermolysis bullosa, pseudohypoparathyroidism and taurodontism. The congenital defects include heart disorders and unilateral facial hypoplasia and hypertrophy. Among the inborn errors of metabolism are: galactosaemia, phenylketonuria, alkaptonuria, erythropoietic porphyria and primary hyperoxaluria. Neonatal disturbances are important in the development of enamel hypoplasia, foremost among these are premature birth and hypocalcaemia. The latter causes postnatal hypoplasias, which, however, are never seen in breast-fed children. Haemolytic anaemia, mostly in conjunction with erythroblastosis foetalis, may cause enamel hypoplasia. In children with neurological disturbances a rather large number have enamel hypoplasias, and these changes may be a significant aid in neurological diagnosis. When the tetracyclines were introduced, many children had these drugs prescribed in the period when the teeth were undergoing mineralization. The result was a yellow-brown stain of the affected teeth. In recent years, however, there appears to have been a reduction in the incidence of tetracycline staining. As for local causes the most important are traumatic injuries and periapical osteitis of primary teeth.

Amelogenesis Imperfecta↗

PubMed1990

Analysis of human enamel genes: insights into genetic disorders of enamel.

A number of inherited craniofacial diseases are known to be associated with gene mutations. Inherited genetic disorders of enamel formation called amelogenesis imperfecta (AI) affect the human population with a prevalence of 1 in 14,000 in the United States. Amelogenins, the major proteins in developing enamel matrix of mammalian teeth, have been suggested to participate in normal enamel matrix biomineralization, as well as with abnormal biomineralization such as seen in AI. The complementary DNA for mouse amelogenin gene (AMEL) has been cloned, characterized, and used as a probe to establish the chromosomal locations of AMEL for mouse and man. The human AMEL gene sequences have been located to the distal short arm p22.1----p22.3 region of the X chromosome, and the pericentromeric region of the Y chromosome. An assignment of human AMEL gene to the X chromosome p22 region together with a recent assignment of the X-linked AI disease locus to the Xp22.2 region support the association of the AMEL-X gene with AI. This also leads us to propose that a mutated AMEL-X gene produces altered amelogenin polypeptide, which is defective in its ability to participate in mineralization of enamel matrix, thus giving rise to the X-linked phenotypes of AI.

Amelogenesis Imperfecta↗

PubMed1997

Human genes for dental anomalies.

The development of the tooth at gene level is beginning to be understood. This paper reviews current knowledge and the advances in research on human genes whose defect leads to dental anomalies. 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. The human amelogenin genes on X and Y chromosomes have been cloned and investigated extensively. Although autosomally inherited forms of AI are more common than the X-linked forms, most studies on the genes causing AI have been performed on the genes of X-linked forms. Recently, the gene for the human tuftelin protein (an enamelin) has been cloned as a candidate gene for the autosomal forms of AI with another gene on chromosome 4 involved in some families. Dentinogenesis imperfecta (DI) may be associated with osteogenesis imperfecta (OI), which is an autosomal dominant bone disease. Most patients with OI have mutations in either the COLIA1 or COLIA2 genes, which encode the alpha 1(I) or alpha 2(I) subunits of type I collagen, the major organic component of bone and dentin. Gene defects causing isolated DI have not been identified. Recently, it was demonstrated that a missense mutation of MSXI, a human homeobox gene, causes autosomal dominant agenesis of second premolars and third molars. Data indicating an important function for MSXI, the mouse counterpart of the human MSXI gene, in mouse tooth development have been accumulating since 1991. Knockout mice lacking this gene exhibited multiple craniofacial anomalies including complete tooth agenesis. 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 predicted EDA protein may belong to a novel class of proteins with a role in epithelial-mesenchymal signaling. Several mutations have been reported in genes causing hypophosphatasia, which is characterized by defective mineralization of the skeletal and dental structures.

Adult↗

PubMed2003

Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature.

The amelogenesis imperfectas (AI) are a genetically heterogeneous group of diseases that result in defective development of tooth enamel. Although X-linked, autosomal dominant and autosomal recessive forms of AI have been clinically characterized, only two genes (AMELX and ENAM) have been associated with AI. To date, three enamelin (ENAM) mutations have been identified. These mutations cause phenotypically diverse forms of autosomal dominant AI. Detailed phenotype-genotype correlations have not been performed for autosomal dominant AI due to ENAM mutations. We identified a previously unreported kindred segregating for the ENAM mutation, g.8344delG. Light and electron microscopy analyses of unerupted permanent teeth show the enamel is markedly reduced in thickness, lacks a prismatic structure and has a laminated appearance. Taken together these histological features support the enamelin protein as being critical for the development of a normal enamel thickness and that it likely has a role in regulating c-axis crystallite growth. Because there is growing molecular and phenotypic diversity in the enamelin defects, it is critical to have a nomenclature and numbering system for characterizing these conditions. We present a standardized nomenclature for ENAM mutations that will allow consistent reporting and communication.

Adult↗

PubMed1999

Evidence for regulation of amelogenin gene expression by 1,25-dihydroxyvitamin D(3) in vivo.

The unique hereditary enamel defect clearly related to the disturbance of one enamel matrix protein is X-linked amelogenesis imperfecta (AI), in which several mutations of amelogenin gene have been identified. The clinical phenotype of many of these subjects shows similarities with enamel defects related to rickets. Therefore, we hypothesized that rachitic dental dysplasia is related to disturbances in the amelogenin pathway. In order to test this hypothesis, combined qualitative and quantitative studies in experimental vitamin D-deficient (-D) rat model systems were performed. First, Western blot analysis of microdissected enamel matrix (secretion and maturation stages) showed no clear evidence of dysregulation of amelogenin protein processing in -D rats as compared with the controls. Second, the ultrastructural investigation permitted identification of the internal tissular defect of rachitic enamel, the irregular absence of intraprismatic enamel observed in -D animals, suggesting a possible link between prism morphogenesis and vitamin D. In addition, the steady-state levels of amelogenin mRNAs measured in microdissected dental cells was decreased in -D rats and up-regulated by an unique injection of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). The present study shows evidences that amelogenin expression is regulated by vitamin D. This is the first study of an hormonal regulation of tooth-specific genes.

Amelogenesis↗

PubMed2003

A prospective clinical trial comparing preformed metal crowns and cast restorations for defective first permanent molars.

AIM: This study investigated two methods for the restoration of permanent molars affected by amelogenesis imperfecta (AI) or severe enamel defects. METHODS: A prospective clinical trial was carried out on 17 subjects affected by AI or severe enamel defects of first permanent molars. A split mouth design was used so that each right or left permanent molar in both jaws was restored using either a preformed metal crown (SSC) or a cast adhesive coping (CAC). Subjects were followed for up to 24 months and assessed for longevity and quality of the restorations. Sequential analysis was used to compare longevity. RESULTS: Records for 42 restorations (19 SSC; 23 CAC) were kept. The split mouth design was possible on 24 occasions (right versus left=14; maxilla versus mandible=10). Three restorations, one SSC (at 6 months) and two CAC (at 2 and 19 months) failed and required replacement. There was no significant statistical difference between the two types of restorations. CONCLUSION: While there was no difference between the two restorations for quality and longevity, the SSC was considerably cheaper to use and needed only one visit, but more tooth tissue was lost in preparation and fitting. The CAC was significantly more expensive but left nearly all of the tooth crown intact. The choice of which restoration to use is indicated by the immediate and long-term needs of each individual patient.

Adolescent↗