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Amelogenesis Imperfecta


What is Amelogenesis Imperfecta?

Amelogenesis imperfecta (AI) (amelogenesis – enamel formation; imperfecta – imperfecta) is a relatively rare group of inherited disorders characterized by abnormal enamel formation. The term amelogenesis imperfecta is reserved for hereditary defects of enamel that are not associated with defects in other parts of the body or other health problems. The prevalence of these conditions has been studied in only a few populations and has been reported to range from 1 in 700 to 1 in 15,000 [1-4].

The AI enamel defects are highly variable and include abnormalities that are classified as hypoplastic (defect in amount of enamel), hypomaturation (defect in final growth and maturation of enamel crystallites), and hypocalcified (defect in initial crystallite formation followed by defective growth) [5]. The enamel in both the hypomaturation and hypocalcified AI types is not mineralized to the level of normal enamel and can be described as hypomineralized. AI can be inherited as an x-linked, autosomal recessive (AR), or autosomal dominant (AD) condition.

The diagnosis and classification of AI has traditionally been based on the clinical presentation or phenotype and the inheritance pattern [6]. Although multiple gene defects responsible for causing AI have been identified since 1990, most of the AI types do not have a known molecular basis. As the molecular defects causing AI are identified, the need for a molecular based nomenclature increases. The rapid identification of multiple mutations in multiple genes has lead to the acceptance of standardized nomenclatures for reporting AI associated mutations at the genomic, cDNA and protein level [7]. The most widely accepted classification system for delineating the AI types subdivides AI into four main types based on the enamel defects and then further divides them into14 distinct subtypes based on clinical appearance (phenotype) and mode of inheritance [6].


Types of Amelogenesis Imperfecta

TYPE I: HYPOPLASTIC AI

All of the hypoplastic AI subtypes are characterized by the primary feature of deficient amount of enamel formed. The decreased amount of enamel varies in the different subtypes and can be characterized by enamel that is pitted, has grooves or furrows, has large areas of missing or very thin enamel surrounded by more normal enamel, or enamel that is very thin over the entire tooth crown. Witkop’s clinical classification of hypoplastic AI recognizes seven subtypes [6].

The four main AI types are shown in Table 1 and brief descriptions of the 14 subtypes are provided. After the name of each subtype are the letters designating mode of inheritance (e.g. AD = autosomal dominant, AR = autosomal recessive, and X-linked). For additional explanation of these different modes of Mendelian Inheritance see the section on Mendelian Inheritance.

Clinical and Hereditary Characteristics of Four Main AI Types (Table 1) [8]
Type
Clinical Appearance
Enamel Thickness
Radiographic Appearance
Inheritance
Hypoplastic
(Type I)
Crowns size varies from small to normal, small teeth may lack proxmial contacts, color varies from normal to opaque white – yellow brown
Varies from thin and smooth to normal thickness with grooves, furrows and/or pits
Enamel has normal to slightly reduced contrast/ thin
Autosomal dominant, recessive, or X-linked
Hypomaturation
(Type II)
Varies from creamy opaque to marked yellow/brown, surface of teeth soft and rough, dental sensitivity and open bite common
Normal thickness with enamel that often chips and abrades easily
Enamel has contrast similar to or > than dentin, unerupted crowns have normal morphology
Autosomal dominant, recessive, or X-linked
Hypocalcified
(Type III)
Opaque white to yellow-brown, soft rough enamel surface, dental sensitivity and open bite common, heavy calculus formation common
Normal thickness with enamel that often chips and abrades easily
Enamel has contrast similar to or < dentin, unerupted crowns have normal morphology
Autosomal dominant, recessive
Hypomaturation/ Hypoplasia/
Taurodontism
(Type IV)
White/Yellow- Brown mottled, teeth can appear small and lack proximal contact Reduced, hypomineralized areas and pits Enamel contrast normal to slightly > dentin, large pulp chambers Autosomal dominant

Modes of Mendelian Inheritance Associated with AI

Autosomal Dominant Inheritance
  • Can have male to male transmission.
  • On average, half of the offspring of an affected individual will be affected. There is a 50% chance for the child of an affected individual to be affected.
  • Affected males and females have similar clinical presentation.
Autosomal Recessive Inheritance
  • Unaffected parents will have affected offspring.
  • On average, one in four offspring of carrier parents will be affected.
  • More likely to occur when parents are related (consanguineous relationship).
X-linked recessive inheritance
  • Do not have male to male transmission.
  • All daughters of an affected male are carriers.
  • Half of the sons born to a carrier female will be affected.
  • Affected males have more severe manifestations than females.
  • Females can show no manifestations to severe manifestations due to lyonization. Females express only one X chromosome per cell with the other X chromosome becoming the bar body. If adequate numbers of cells express the X chromosome carrying the mutant allele, they will have varying degrees of the enamel defect.

Amelogenesis Imperfecta Research

Since the first enamel matrix associated gene (AMELX) was identified in the late 1980’s [26] and the first AI associated mutation was reported in 1990 [36, 37], there have been over a 25 different AI associated mutations identified. This research confirms the genetic heterogeneity of AI and has greatly advanced our understanding of these conditions. There are now known to be mutations in four different genes that are associated with AI (i.e. AMELX, ENAM, KLK4, MMP20). Although a DLX3 mutation has been reported as causative of hypomaturation AI with taurodontism this mutation is actually asscociated with a variant of the tricho-dento-osseous syndrome.  Linkage studies on large families with autosomal dominant AI show no evidence of linkage to any of these or other known AI candidate genes indicating that other, as yet to be discovered, genes will be associated with AI.

As the genetic mutations associated with the different AI types become known, our ability to accurately diagnose the different AI conditions is becoming markedly improved. The similarity in clinical features makes differentiating some AI types at the clinical level difficult. Correlation of the genetic mutations with the clinical phenotypes of each AI subtype will be invaluable for managing patients with AI. This knowledge also allows us to better predict which AI types are associated with problems such as calculus formation and skeletal open bites and for selecting the most optimal treatment approaches.

Amelogenin (AMELX) Mutations

Over a 14 mutations have been identified in the AMELX gene. Different phenotypes are associated with different AMELX mutations depending on the mutations effect on the amelogenin protein. All the AMELX mutations resulting in a loss of the C-terminus of the protein or total loss of the protein (signal peptide mutations and large deletions) have hypoplastic enamel. Mutations causing single amino acid changes cause hypomaturation defects that in some cases also have hypoplastic enamel. For a review of the phenotype-genotype associations in X-linked AI see Wright et al. 2003 [38].

The AMELX mutations are presented in Table 2 using a standardized nomenclature [7]. The genomic, cDNA and deduced protein are shown in the first three columns. The accession numbers for the genomic and cDNA sequences are shown below the table.

AMELX Mutations (Table 2)
Genomic DNA^ cDNA+ Protein* Male Phenotype Reference
g.2T>C c.2T>C p.M1T Smooth Hypoplastic (normal mineralization) Simmer et al. 2004
g.11G>C c.11G>C p.W4S Smooth Hypoplastic (normal mineralization) Simmer et al. 2004
g.11G>A c.11G>A p.W4X Smooth Hypoplastic (normal mineralization) Sekiguchi et al. 2001
g.14_22del c.14_22del p.I5_A8delinsT Smooth Hypoplastic(normal mineralization) Lagerström-Fermer et al. 1995
g.1148_54del c.55_54del p.18del Hypomaturation(some hypoplasia) Lagerström et al. 1991
g.3455C>T c.152C>T p.T51I Hypomaturation(some hypoplasia) Lench and Winter 1995
g.3458delC c.155delC p.P52fsX53 Hypomaturation(some hypoplasia, variable) Aldred et al. 1992; Lench et al. 1994
g.3781C>A c.208C>A p.P70T Hypomaturation(some hypoplasia) Collier et al. 1997; Hart et al. 2000
g.3803A>T c.230A>T p.H77L Hypomaturation Hart et al. 2001
g.3958delC c.385delC p.H129fsX187

Smooth Hypoplastic

Sekiguchi et al. 2001
g.3993delC c.420delC p.Y141fsX187 Smooth Hypoplastic Greene et al. 2000
g.4046delC c.473delC p.P158fsX187 Smooth Hypoplastic Lench and Winter 1995
g.4114delC c.541delC p.L181fsX187 Smooth Hypoplastic(some hypomineralization) Kindelan et al. 2000; Hart et al. 2001
g.4144G>T c.571G>T p.E191X Smooth Hypoplastic Lench and Winter 1995

^ Genomic reference sequence accession number AY040206.
+ cDNA Amelogenin reference sequence accession number Af436849
* Initiator methionine as the +1 position; fs = frameshift; X = stop
[37, 39-48]

Enamelin (ENAM) Mutations

Mutations in the ENAM gene are now known to be associated with at least two clinically distinct AI types. These traits are most often transmitted in an autosomal dominant manner with variable expression being noted. One recent family was reported to be transmitted as autosomal recessive. Four different mutations have been identified to date. All of these mutations result in hypoplastic AI. Mutations resulting in loss of most of the protein such as the p.K53X result in local pitting presumably due to haploinsufficiency. In contrast mutations that cause a substantion portion of an altered protein to be translated produced a generalized thin enamel phenotype presumably due to a dominant negative effect. The ENAM mutations are shown using a standardized nomenclature in Table 3.

ENAM Mutations (Table 3)
Genomic DNA^ cDNA+ Protein* Phenotype Reference
g.2382A>T c.157A>T p.K53X Local hypoplastic Mardh [11]
g.6395G>A IVS7+1G>A; c.534+1G>A p.A158_Q178del Generalized thin hypoplastic Rajpar [13]
g.8344delG IVS8+1delG;c.588+1delG p.N197fsX277 Generalzied thin hypoplastic Kida 2003 [14] Hart 2003 [15]
g.13185_13186insAG c/1258_1259insAG p.P422fsX448 Generalized thin hypoplastic Hart 2004 [16]

a Reference sequence GenBank accession no. AY167999; the A of the initiator ATG is taken as +1.
b Reference sequence GenBank accession no. AF125373; the A of the initiator ATG is taken as +1.
c Initiator methionine as the +1 position.

Enamelysin (MMP20) and Kallikrein 4 (KLK4)Mutations

Mutations in the two major proteinases (MMP20 and KLK4) involved in processing the enamel matrix during development and mineralization are associated with autosomal recessive pigmented hypomaturation amelogenesis imperfecta. The enamel is of normal thickness but has a reduced mineral content and increased protein content. The trait is transmitted in an autosomal recessive manner. MMP20 codes for a matrix metalloproteinase that is highly expressed during the secretory stage of enamel formation. Kallikren 4 codes for a serine proteinase that is maximally expressed by ameloblasts during the maturation stage of enamel development. While mutations in both the major proteinases have been identified, evaluation of families with autosomal recessive pigmented hypomaturation AI have not shown mutations in these two genes suggesting this AI subtype is genetically heterogeneous.

MMP20 and KLK4 Mutations (Table 4)
MMP20 Mutations
Genomic DNA^ cDNA+ Protein* Phenotype Reference
g.30561A>T c.954-2A>T or c.IVS6-2A-T p.I319Fs338X or p.I319X Pigmented Hypomaturation Decreased Mineral Kim et al. 2005
g.16250T>A c.678T>A p.H226Q Hypomaturation Hart et al. in press
KLK4 Mutations
g.2142G>A c.458G>A p.W153X Pigmented Hypomaturation Decreased Mineral Hart et al. 2004

a Reference sequence GenBank accession no AF228497; the A of the initiator ATG is taken as +1.
b Reference sequence GenBank accession no NM_004917; the A of the initiator ATG is taken as +1.
c Initiator methionine at the +1 position.

FAM83H

The most recently identified gene shown to cause AI is the FAM83H gene. This gene is located on chromosome 8q24 and causes autosomal dominant hypocalcified AI (ADHCAI) in families around the world [63-65]. The importance of the FAM83H gene is evident from the resulting phenotype that is characterized by a marked reduction in mineralization of the enamel giving rise to the designation as hypocalcified. The discovery that FAM83H causes ADHCAI provides new knowledge of the molecular basis of the most common AI type in North America. In our population ADHCAI accounts for 25% the families with known AI types and 35% of the individuals with AI.

The role of the FAM83H gene and protein during enamel formation remains unknown. The gene is expressed in many tissues, however, all mutations reported to date result only in enamel abnormalities, suggesting this gene is essential for enamel formation but not as critical in other tissues [1, 4]. FAM83H codes for an 1179 amino acid protein whose function is unknown. A potential transactivation domain was identified in silico, suggesting that FAM83H could serve as a transcription factor.

Characterization of the phenotype in ADHCAI is variable within and between families and we have identified different ADHCAI phenotypes associated with specific FAM83H mutations. Most individuals with FAM83H mutations are characterized by both the primary and permanent teeth having a yellow brown discoloration and enamel that tends to readily fracture from the teeth (generalized phenotype). The enamel has a variable but markedly decreased mineral content (40 to 70% mineral per volume) and an increased protein content that is not proline rich as is seen in the hypomaturation AI types [5]. Individuals having mutations causing truncation of the protein at or prior to amino acid 677 all display a generalized ADHCAI. Interestingly, individuals with mutations affecting the FAM83H protein at amino acid 694 or later have a localized ADHCAI that affects primarily, but not exclusively the cervical third of the crown [3]. We hypothesize that this unique phenotype is associated only with mutations that result in production of a longer and potentially less dis-functional FAM83H protein compared with mutations truncating the protein at amino acid 677 or lower that result in generalized ADHCAI. We believe the generalized ADHCAI results from a dominant negative effect and have shown that the mutant mRNA is not degenerated by non-sense medicated decay. There are now 13 mutations reported in FAM83H that cause ADHCAI as shown in Table 5.

FAM83H Table 5
cDNA Protein Phenotype Reference
c.860C>A p.S287X Generalized Wright 2009
c.891T.A p.Y297X Generalized Lee 2008
c.923_924delTC p.L308fsX323 Generalized Wright 2009
c.973C.T p.R325X Generalized Kim 2008
c.1192C.T p.Q398X Generalized Kim 2008
c.1243G.T p.E415X Generalized Lee 2008
c.1330C.T p.Q444X Generalized Hart 2009
c.1366C.T p.Q456X Generalized Hart 2009
c.1380G.A p.W460X Generalized Lee 2008
c.1408C>T p.Q470X Generalized Wright 2009
c.1872_1873delCC p.L625fsX703 Localized Wright 2009
c.2029C.T p.Q677X Generalized Lee 2008
c.2080G>T p.E694X Localized Wright 2009

The Figure below shows the difference between localized and generalized HCAI phenotypes and the different protein designations associated with each phenotype.


Figure 5

Table of AI Types and Currently Known Genes

Witkop Classification Modified Classification OMIM # Gene
TYPE I Hypoplastic
IA-hypoplastic pitted (AD) AD generalized hypoplastic ? LAMB3
IB-hypoplastic local (AD) AD generalized hypoplastic 104500 ENAM
IC–hypoplastic local (AR) AR local hypoplastic 204650 ENAM
ID-hypoplastic smooth (AD) AD generalized thin hypoplastic ? ?
IE-hypoplastic smooth (X linked) X linked generalized thin hypoplastic 301200 AMELX
IG—enamel agenesis (AR) AR generalized thin hypoplastic
(enamel-renal syndrome)
614253
204690
FAM20A
TYPE II Hypomaturation
IIA—pigmented hypomaturation (AR) AR pigmented hypomaturation (IIA1) 204700
(IIA2) 612529
(IIA3) 613211
(IIA4) 614832
MMP20
KLK4
WDR72
C4ORF
IIB-hypomaturation (X linked) X linked hypomaturation 301200 AMELX
IIC-snowcapped (X linked) X linked snowcapped 301200 AMELX
TYPE III Hypocalcified
IIIA- hypocalcified (AD) AD hypocalcified 130900 FAM83H
IIIB—hypocalcified (AR) AR hypocalcified Not listed SLC24A4
TYPE IV Hypomaturation-Hypoplastic with Taurodontism
IVA Hypomaturation-Hypoplastic
with Taurodontism (AD)
(AD) Tricho-dento-osseous
syndrome
AI 104530
TDO 190320
DLX3
IVB- Hypomaturation-
Hypoplastic with Taurodontism (AR)
? ? ?

 

For additional information on the AI associated genes and molecular defects in AI see the OMIM Web site.


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