Amelogenesis imperfecta (imperfect Amelogenesis) - Genes AMELX, ENAM, MMP20 and FAM83H

Amelogenesis imperfecta is a disorder of tooth development that causes the teeth are unusually small, abnormal color (yellow, brown or gray), grooved and prone to rapid wear and breakage. Other dental anomalies are also possible. These defects vary between individuals affected and can affect both primary teeth and permanent teeth.

They have been described at least 14 forms amelogenesis imperfecta. These types are distinguished by their specific dental anomalies and their pattern of inheritance. Furthermore, amelogenesis imperfecta may occur as an isolated condition without other signs and symptoms or may occur as part of a syndrome that affects multiple body parts.

This may be due to mutations in AMELX, ENAM, MMP20 and FAM83H genes. The AMELX, ENAM, and MMP20 genes encode proteins that are essential for normal development of teeth. Most of these proteins are involved in enamel formation. Furthermore, although the function of the protein encoded by the gene FAM83H is unknown, it is believed that is also involved in enamel formation. Mutations in any of these genes altering protein structure or inhibit the coding of any of them. As a result, the tooth enamel is abnormally thin, and may have a yellow or brown. Teeth with defective enamel are weak and easily damaged. Mutations in AMELX, ENAM, MMP20 and FAM83H genes account for only about half of all cases of the disease, although most of these cases are due to mutations in the gene FAM83H. In other cases, the genetic cause has not been identified.

The AMELX (amelogenin, X-linked) gene located on the short arm of the X (Xp22.31-p22.1) chromosome codes amelogenin protein, which is essential for normal development of teeth. Amelogenin is involved in enamel formation, consisting mainly of mineral crystals. These microscopic crystals are arranged in organized enamel beams providing strength and durability. Although the exact function of the amelogenin not well understood, it appears that separates and supports the crystals as they grow. Amelogenin crystals is removed from developing when no longer needed, leaving the mature enamel, containing very little protein. A copy gene amelogenin is in each sex chromosome (X and Y). The AMELX gene, located on chromosome X, encoding most of amelogenin body. Copy amelogenin gene on the Y chromosome, AMELY synthesizes very little amelogenin and is not necessary for the formation of enamel.

They have identified at least 23 AMELX gene mutations in people with imperfect amelogenesis. Some of these genetic changes lead to the synthesis of an abnormal version of amelogenin protein may interfere with the formation and organization of the enamel crystals, while other changes inhibit any amelogenin protein coding. Males who inherit an altered copy of the gene AMELX have little amelogenin, so their teeth develop almost without enamel to cover and protect them . Women who inherit an altered copy of the gene AMELX have a mild disease because they have a normal copy of the gene on the other chromosome X to produce amelogenin. Their tooth enamel can have structural defects such as a distinctive pattern of vertical grooves.

The ENAM (enamelin) gene, located on the long arm of chromosome 4 (4q13.3), encoding the protein synthesis enamelin, which is essential for normal development of teeth. Although the exact function is not well understood enamelin, this protein plays a key role in the formation and growth of crystals in the enamel development. At least 14 mutations in the ENAM gene have been identified in people with imperfect amelogenesis both autosomal dominant and autosomal recessive. In the autosomal dominant form, a copy of the gene in every cell ENAM altered. These mutations have a variety of effects on enamel formation. Some of these mutations reduce the amount of encoded enamelin from a copy of the gene. Other mutations result in the synthesis of an abnormally short version enamelin in which are absent certain critical regions. A reduced amount of enamelin or an altered version of the protein can cause serious problems in developing enamel or mild, such as horizontal grooves in the teeth defects. In autosomal recessive, both copies of the gene are altered ENAM in each cell. These mutations result in the synthesis of an abnormal version of enamelin altering enamel development. People who inherit two mutated copies of ENAM gene have severe defects in the glaze; Consequently, this protective coating can be very thin or be absent.

The MMP20 (matrix metallopeptidase 20) gene, located on the long arm of chromosome 11 (11q22.3), enamelysin encoding protein which is essential for normal development of teeth. Like the amelogenin and enamelin proteins, enamelysin is involved in enamel formation. Although certain proteins needed to form and arrange the enamel crystals, these proteins must be subsequently removed to harden the enamel. In this sense, the enamelysin cleaves other proteins involved in the formation of the enamel, such as amelogenin and ameloblastin in smaller units. Cleavage of these proteins makes it easy to remove when no longer needed. They have identified at least seven mutations in the MMP20 gene in people with autosomal recessive form of imperfect amelogenesis. These mutations inhibit functional coding enamelysin. Without functional enamelysin, amelogenin and other proteins are cleaved during enamel formation. Because these proteins remain in the enamel, it does not harden during formation, resulting in an unusually rough and discolored, prone to breakage defective enamel.

The FAM83H (family with sequence similarity 83 member H) gene, located on the long arm of chromosome 8 (8q24.3), encodes the synthesis of a protein whose function is not well understood. The protein is found in various cell types, including ameloblasts, producing tooth enamel. It is believed that FAM83H protein is involved in enamel formation, although its role in this process is unknown. We found at least 20 mutations in the gene FAM83H in an autosomal dominant form of amelogenesis imperfecta. These mutations result in the synthesis of an abnormally short protein. While the normal protein found in the cytoplasm, the protein is altered in the nucleus of the cell. It is believed that the altered protein encoded from the mutated copy of the gene interferes with the function of the normal protein encoded from the unmutated copy of the gene (such mutations are described as "dominant negative"). However, it is not clear how the altered protein leads to the development of an unusually thin, with a rough enamel and discoloration.

Amelogenesis imperfecta may have different inheritance patterns depending on which gene is altered. Many cases are due to mutations in the gene FAM83H and are inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. Some cases due to mutations in the gene ENAM also have an autosomal dominant inheritance pattern. Besides autosomal dominant inheritance, this process may be patterned autosomal recessive inheritance when due to mutations in the gene ENAM or MMP20 gene. Autosomal recessive inheritance means both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. About 5% of cases of imperfect amelogenesis are due to changes in the AMELX gene and are inherited in a pattern linked to chromosome X. An alteration is considered X - linked if the mutated gene responsible for the disease is in the X chromosome, one of the two sex chromosomes. In most cases, men with imperfect X - linked amelogenesis have more severe than women with this form of the disease dental anomalies. Other cases are due to imperfect amelogenesis new genetic mutations and occur in people with no history of disease in your family.

Tests in IVAMI: in IVAMI perform detection of mutations associated with amelogenesis imperfecta, by complete PCR amplification of the exons of AMELX, ENAM, MMP20 and FAM83H genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).