Amelogenesis Imperfecta

Just as the classification of AI is complex, so too is the contribution of genetics to these disorders. Changes (mutations) in specific genes have been identified as the cause of 19 subtypes of AI. The causal gene and mode of inheritance for these subtypes based on the OMIM (Online Mendelian Inheritance in Man) are listed below:

Type I hypoplastic AI

• Type IA: autosomal dominant inheritance, LAMB3 mutation
• Type IB: autosomal dominant inheritance, ENAM mutation
• Type IC: autosomal recessive inheritance, ENAM mutation
• Type IE: X-linked dominant inheritance, AMELX mutation
• Type IE, X-linked 2: X-linked inheritance, gene unknown
• Type IF: autosomal recessive inheritance, AMBN mutation
• Type IG: autosomal recessive inheritance, FAM20A mutation
• Type IH: autosomal recessive inheritance, ITGB6 mutation
• Type IJ: autosomal recessive inheritance, ACPT mutation

Type II hypomaturation AI

• Type IIA1: autosomal recessive inheritance, KLK4 mutation
• Type IIA2: autosomal recessive inheritance, MMP20 mutation
• Type IIA3: autosomal recessive inheritance, WDR72 mutation
• Type IIA4: autosomal recessive inheritance, C4orf26 mutation
• Type IIA5: autosomal recessive inheritance, SLC24A4 mutation
• Type IIA6: autosomal recessive inheritance, GPR68 mutation

Type III hypocalcified AI

• Type IIIA: autosomal dominant inheritance, FAM83H mutation
• Type IIIB: autosomal dominant inheritance, AMTN mutation
• Type IIIC: autosomal recessive inheritance, RELT mutation

Type IV hypomaturation/hypoplasia/taurodontism AI

• Type IV: autosomal dominant inheritance, DLX3 mutation

Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

If a male with an X-linked disorder can reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive.

Mutations in the AMELX, ENAM, MMP20 and FAM83H genes can cause amelogenesis imperfecta. The AMEX, ENAM, and MMP20 genes provide instructions for making proteins that are essential for normal tooth development. Most of these proteins are involved in the formation of enamel, which is the hard, calcium-rich material that forms the protective outer layer of each tooth. Although the function of the protein produced from the FAM83H gene is unknown, it is also believed to be involved in the formation of enamel. Mutations in any of these genes result in altered protein structure or prevent the production of any protein. As a result, tooth enamel is abnormally thin or soft and may have a yellow or brown color. Teeth with defective enamel are weak and easily damaged.

Mutations in the genes described above account for only about half of all cases of the condition, with FAM83H gene mutations causing the majority of these cases. In the remaining cases, the genetic cause has not been identified. Researchers are working to find mutations in other genes that are involved in this disorder.