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Amelogenesis Imperfecta - Genes and Enamel Formation
| Enamel is the hardest, most mineralized tissue in the human body. Enamel is made up of very small mineralized crystallites (small crystals) that are oriented in a specific pattern to form enamel prisms (Figure 19). The prisms are organized in an interlocking pattern adding to the enamel’s fracture and wear resistance. |
figure19 |
| Human enamel is approximately 97% mineral by weight with approximately 1% protein and 2% water. The enamel mineral is composed of a carbonate substituted hydroxyapatite mineral that has varying concentrations of trace elements such as fluoride, chloride, sodium and magnesium. The enamel on a human tooth takes years to form and involves a complex and highly orchestrated process of laying down a protein matrix, processing this matrix in a controlled fashion and regulating the ion concentration of the mineralizing environment. Many of these processes are controlled directly by the ameloblasts, the cells that produce enamel. There are many excellent reviews written on enamel formation for those seeking further information on this topic [22-25] | |
There are thousands, to potentially over 10,000 genes involved in the formation of human enamel. We estimate from our research on forming teeth using microarrays that the number is 10,000 or more genes are involved in tooth formation. Many of the genes known to be involved in tooth formation can be reviewed at (http://bite-it.helsinki.fi/).
Genes involved in enamel formation are expressed in a highly regulated fashion at specific times and locations. Genes produce proteins that regulate gene expression, cell function and can be secreted from the enamel forming cells (ameloblasts) to form the matrix or template for the developing enamel. Some of the proteins secreted from ameloblasts regulate the size, shape and orientation of the growing enamel crystallites and thus contribute to the ultimate structure and composition of the enamel. Several genes and gene products that are either known to be associated with AI or are thought to be likely candidate genes for AI types where the associated gene remains to be identified are briefly reviewed in the following sections.
Amelogenin: (product of AMELX and AMELY genes located on the X and Y chromosomes) is the most abundant protein in developing enamel [26, 27]. While its exact role in enamel formation is not fully understood, it is thought to be crucial for regulating the size and shape of the mineralizing enamel crystallites. Multiple human mutations in the AMELX gene are associated with different AI types. There are no known AMELY mutations and it is thought that only about 10% of amelogenin mRNA transcripts comes from the AMELY gene. A transgenic mouse lacking expression of the AMELX gene has only a very thin covering of enamel that lacks a prismatic structure that is similar in appearance to some humans having AMELX mutations[28].
Ameloblastin: (product of AMBN gene located on chromosome 4) is another enamel associated protein that appears to be the second most abundant enamel matrix protein [29]. The function of this protein is unknown but it is considered a likely candidate for being associated with some AI types.
Enamelin: (product of ENAM gene located on chromosome 4) is secreted by amelobasts in relatively low amounts [30, 31]. It has been speculated that this protein could interact with amelogenin or other enamel matrix proteins and be important in determining growth of the length of enamel crystallites. Multiple mutations ENAM gene mutations are associated with different autosomally inherited AI types.
Enamelysin: (MMP20 gene located on chromosome 11) is a proteinase that cleaves amelogenin and is thought to be the major proteinase involved in processing the enamel matrix proteins [32, 33]. The enamelysin knockout mouse has a reduced enamel thickness, poorly mineralized enamel and the enamel lacks a prismatic structure.
Kalikryn 4: (KLK4 gene located on chromosome 19) is a proteinase that is secreted predominantly during the maturation stage of enamel development [34]. This aggressive proteinase could be responsible for processing any proteins not cleaved by enamelysin. Removal of this protein during maturation is critical to allow the enamel crystallites to grow and mature fully and the enamel to mineralize completely. Mutation of KLK4 is associated with autosomal recessive hypomaturation AI that is characterized by poorly mineralized enamel.
There are other enamel related genes, such as tuftelin, that have been proposed as candidate genes for AI [35]. It is highly probable that genes not yet even known to be important in enamel formation are associated with one or more of the AI types where the molecular defect is not yet known.
For more information on genes in teeth link to http://bite-it.helsinki.fi/.