Your sister has noticed that the teeth of her young son are discoloured and has taken him to the dentist. After a series of tests, the condition of X-linked amelogenesis imperfecta is diagnosed. She asks you, a dental student, to explain the reason for this condition. Particularly, she would like to understand why, in this condition, the enamel is malformed, how the enamel differs from normal and the reason her son, but not her, or her husband is affected.
1. To explain and understand normal enamel formation.
2. To identify the different types of AI and their presentation.
3. To describe the genetic code and various types of genetic mutations that can be found.
4. To understand and describe the phrases; autosomal dominant inheritance, autosomal recessive inheritance and X-linked recessive inheritance.
5. To identify the genes associated with AI.
Amelogenesis imperfecta is a hereditary disorder that affects tooth development and results in the abnormal formation of tooth enamel. In the above scenario our ‘nephew’ has been diagnosed with ‘X-linked amelogenesis imperfecta’. Below I will explore the proposed learning outcomes and take a closer look at the inherited disease.
Explain and understand normal enamel formation.
The teeth are composed of three mineralised tissues; enamel, dentine and cementum, which surround the inner unmineralised dental pulp. 
The dental pulp is the only ‘living’ part of the tooth and is made up of connective tissue, odontoblasts and nerves. It supplies the outer mineralised layers with a supply of organic compounds and the odontoblasts help with the creation and repair old dentin. The nerves inside the pulp are also very sensitive and alert an individual of any injury or trauma that may occur. If the pulp is exposed to bacteria, infections are likely.  http://www.dentalhealth.ie/common/images/legacy/dhp/pic_stuctureoftooth.gif
Cementum can be found below the gum line covering the dentin and root of the tooth. It helps to anchor the tooth and protect the root. It is continuously formed through life by cementoblasts in the dental pulp as it prone to destruction. 
 FIG.1 Basic tooth structureDentine is made up of tiny tubules and is the most abundant of the three mineralised tissues. It acts as support beneath the enamel covering and has a protective function to the dental pulp. Dental pulp, cementum and dentine are all derived from the mesencymal origin. 
 FIG.2 Enamel structure The head is orientated superficially and the tail towards the tooth root
Lastly enamel which is derived from the ectoderm is made up of primarily crystalline calcium phosphate and is the outermost component of the tooth and covers the dental crown. The calcium hydroxyapatite enamel crystals are arranged as keyhole shaped rods that span the full thickness of the enamel layer (see fig.2). The enamel crystals have a parallel orientation and any gaps between the rods are filled with further crystals. Enamel is the hardest most mineralised structure found in the human body.  
Enamel is formed by the process of amelogenesis after dentine is formed in the process of dentinogenesis. There are four main stages to amelogenesis; Presecretory, secretory, maturation and post maturation. 
 FIG.3 Basic tooth structureThe presecretory stage starts with proliferation of the oral epithelium to form the dental lamina, further proliferation with occur at the site of each future tooth and there will be an outgrowth of cells; this is called the bud stage. This bud of cells then enlarges and develops a cavity in the cap stage and further growth and development will lead to the development of four recognisable layers in the bell stage. Finally the internal enamel epithelium will cease to divide and the dental lamina will degenerate leaving being the early developing tooth. 
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‘In the secretory stage a partially mineralised enamel matrix is deposited directly on the surface of the previously formed dentin by adjacent secretory stage ameloblasts.’  The organic partially mineralised matrix is produced as a result of the combined actions of the rough endoplasmic reticulum, Golgi apparatus and secretory granules. The ameloblasts will move away when the first layer of enamel is deposited on the dentine allowing the Tomes’s process to develop at the secretory pole of each ameloblasts. The Tomes’s process is responsible for the formation of enamel rods as it lays down the crystals of the enamel matrix. The ameloblasts lie adjacent to the stratum intermedium which contains alkaline phosphotase which is responsible for calcification of the tooth enamel. These ameloblasts continue to produce the enamel matrix until full thickness is reached. 
‘Maturation of the partially mineralised enamel matrix involves the removal of organic material and the continuous influx of calcium and phosphate.’  Maturation stage ameloblasts differentiate from secretory stage ameloblasts and they now contain high numbers of mitochondria to carry out their function as a transport epithelium moving substances into and out of the maturing enamel. The maturing enamel matrix contains four main types of protein; amelogenins, ameloblastins, enamelins and tuftelins. The amelogenins are important in maintaining the spaces between the enamel rods and the ameloblasts control the elongation of the enamel crystals, both of these proteins are removed from the mature enamel. Enamelins undergo cleavage as the enamel matures and will only be found on the surface of the crystals.Tuftelins are present in mature enamel and responsible for hypomineralisation.  
In the final stage of post maturation the enamel organ will degenerate and the tooth will erupt and become exposed to the oral environment. 
Identify the different types of AI and their presentation.
Amelogenesis imperfecta is a group of hereditary disease that affects both the primary and secondary dentition. It results in the enamel becoming hypoplastic, hypomineralised, discoloured and sensitive. 
There are four main types of amelogenesis imperfecta (AI) that have been identified because of their differences in enamel defects that present in patients.
In Hypoplastic AI (type1) the enamel is of normal colour but much thinner as the enamel has not formed to normal thickness, the enamel can also have pits and grooves due to the disturbance in differentiation of ameloblastins. In hypomaturation(type 2) AI the teeth are of normal shape but have a mottled, dark, opaque appearance and chip away easily from the underlying dentine because of a change to the rod structure. Hypocalcified AI (type 3) has poor enamel mineralisation and a defect in its matrix structure making it very soft and susceptible to abrasion; its appearance is dark and chips easily.   (see fig.4).http://www.ojrd.com/content/figures/1750-1172-2-17-1-l.jpg
Finally hypoplasia (type 4) AI is a combination of hypoplastic and hypomaturation AI. It is characterised by a reduction in enamel thickness and the enamel has a yellow brown mottled appearance. 
 FIG.4 Phenotypic descriptions of amelogenesis imperfecta. hypoplastic (a, b, c, d), dysmineralised (e, f), hypocalcified (g, h) hypomineralised form (e and f) The hypomaturation forms (g, h)
Describe the genetic code and various types of genetic mutations that can be found.
‘Genetic information is encoded in the base sequence of DNA molecules as a series of genes.’ ‘The genetic code describes how base sequences are interpreted into amino acid sequences during protein synthesis via transcription and translation.’ 
The DNA sequence of a gene is divided into a set of three bases called a codon (see fig.5). Each codon gives rise to a particular amino acid or a stop signal. The genetic code is referred to as ‘degenerate’ because each amino acid is encoded by more than one codon; there are 64 possible combinations of codons from the 4 nucleotide bases (Adenine, guanine, cytosine and uracil or thymine) but only 20 different amino acids. (See fig.6)http://2.bp.blogspot.com/-i-CYqAFf61o/TZXYoBQmXrI/AAAAAAAAB5g/5PmMdfOP1PQ/s1600/genetic-code-1.jpg
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This degeneracy minimises the possible effects of mutations as alterations to the base sequence are less likely to change the amino acid so changes to the protein structure and function are avoided, this is known as a silent mutation. Protein synthesis always starts with the initiation codon ‘AUG’ which encodes the amino acid methionine but this is later removed. Protein synthesis is terminated by the any of the three stop codons; UAG, UGA and UAA. 
DNA mutations can however cause genetic disorders and cancers. A gene mutation occurs when there is a change in the DNA sequence that makes up a gene; these can be classified as either point mutation which involves the alteration of a single base or gross mutations which often involve the alteration of longer DNA sequences.
There are several types of point mutations. Missense mutations occur when a single base is altered or substituted and a different amino acid is produced. Nonsense mutations result in translation ending prematurely because a nucleotide base has been substituted for another resulting in a stop codon and frameshift mutations result after a single base is either deleted or inserted which causes the ribosome to read a new set of codons which will alter the complete amino acid chain produced.(see fig,7) All these changes to the DNA sequence will alter the amino acid chain and subsequently have a serious effect on the protein produced and effect how well it will work or how it will carry out a specific task. Gross mutations have the same implications and also experience insertion and deletion but this is of several bases at a time. 
Figure 4: If the number of bases removed or inserted from a segment of DNA is not a multiple of three (a), a different sequence with a different set of reading frames is transcribed to mRNA (b).
 FIG.7 Frameshift mutations
If the number of bases removed or inserted from a segment of DNA is not a multiple of three (a), a different sequence with a different set of reading frames is transcribed to mRNA (b).
Identify the genes associated with AI.
Faulty alleles of the genes AMELX, MMP20, KLK-4 and ENAM cause the disease amelogenesis imperfecta. These genes usually provide the genetic instructions for the production of proteins that are essential for the healthy formation of enamel. The mutations of these genes have caused a change in the nucleotide base sequence and as a result the protein structure is altered making them work ineffectively or not at all, in turn this has a variety of effects on the enamel formation. 
The AMELX gene is located on both of the sex chromosomes, X and Y and provides instructions for the protein amelogenin which is essential for normal tooth development as is separates and supports the hydroxyapatite crystals as they mature. Mutations in AMELX have been found to cause X-linked amelogenesis imperfecta because of the change in structure to amelogenin. 
The ENAM gene provides instructions for the production of the protein enamelin and mutations of this gene can be found in both patients with autosomal dominant AI and autosomal recessive AI. (see below)
MMP20 is responsible for the protein enamelysin mutations in this gene are inherited via the autosomal recessive pathway and KLK-4 mutations are responsible for hypomaturation AI. 
Understand and describe the phrases; autosomal dominant inheritance, autosomal recessive inheritance and X-linked recessive inheritance.
Humans have 22 pairs of autosomal homologous pairs of chromosomes and one pair of sex chromosomes; X and Y. Females have two X chromosomes where as males have one X and one Y chromosome. 
There are three patterns of single gene disorders that allow faulty alleles (version) to be passed between generations. These include autosomal dominant, autosomal recessive and X-linked. Autosomal dominant genes
 FIG.8 Autosomal inheritance
In autosomal dominant disorders only one faulty allele needs to be passed from the parents to the offspring for them to be affected by the disease. The affected child will also have one normal allele of the gene making them heterozygous. The affected children’s’ offspring will also have a 50% chance of inheriting the affected allele. (see fig.8)
In autosomal recessive disorders however the likeliness of being affected by the disease is only 25% and both parents must possess at least one of the mutated alleles. (See fig.9)This is because in recessive orders both inherited alleles must be mutants to show an effect in the offspring. There still is a 50% chance of being a carrier (if you have one healthy and one effected allele). http://retinaaustraliansw.com.au/images/AutosomalRecessiveInheritance.gif
 FIG.10 X-linked inheritance
Illustration showing X-linked recessive inheritance pattern with carrier mother
In X-linked disorders the faulty allele is present on the X chromosome. As males only have one X chromosome they only need one copy of the allele to have the disease, they are hemizygous. Females however must have two copies of the faulty allele (homozygous) to be affected and so are in most case carriers. A female carrier has a 50% chance of their daughters being carriers and a 50% chance of their sons being affected by the disease. (See fig.10)
Amelogenesis imperfecta has different modes of inheritance. Hypoplastic (Type I) and Hypomaturation (Type II) AI can be inherited by all three modes of the above inheritance patterns. Hypocalcified (Type III) AI is not inherited via the X-linked pathway and Hypoplasia (Type IV) AI is only passed between generations via the autosomal dominant pathway and only one faulty allele has to be passed to the offspring for them to be affected by amelogenesis imperfecta. 
Our nephew has been diagnosed with X-linked amelogenesis imperfecta. Taking in account the above information we can now conclude the reason why he but not his parents are affected by the disease is because our ‘sister’ must be a carrier of the faulty allele of the gene AMELX. Males are hemizygous so the possibility of the father possesing the faulty allele has been ruled out or he would too be affected by the disease.
One can also assume that he is suffering from either hypoplastic AI or hypomaturation AI as the other two types are not inherited via the X-linked pathway.
The treatment of amelogenesis imperfecta will depend on the severity of the condition but it is usually to treat the aesthetic symptoms so crowns may be given to hide the displeasing characteristics of the malformed enamel.
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