Amelogenesis Imperfecta, Type Ie


A number sign (#) is used with this entry because this form of hypoplastic amelogenesis imperfecta (AI1E) is caused by mutation in the gene encoding amelogenin (AMELX; 300391).


Amelogenesis imperfecta is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).

Clinical Features

Witkop (1957) was the first to describe a hypomaturation form of AI. In this form, both dentitions are affected. In males, primary teeth are opaque ground-glass white, and secondary teeth are mottled yellow-brown and white. Enamel is of normal thickness, moderately soft, and does not contrast from dentin on x-ray. The teeth chip and abrade more easily than normal teeth, but the loss of enamel is not as rapid as in the hypocalcified form (Witkop and Sauk, 1976). Because of the appearance of the teeth in this form, referred to as snow-capped (Witkop and Sauk, 1976; Escobar et al., 1981) in its most marked form, confusion with fluorosis sometimes occurs. The condition has been observed in areas essentially devoid of fluoride in drinking water and has occurred in family members through 3 generations who have resided in different areas of the country (Witkop and Rao, 1971).

Rushton (1964), Witkop (1967), and Sauk et al. (1972) pointed out differences in affected males and heterozygous females which may be based on the Lyon phenomenon. Affected males have only a very thin, smooth layer of enamel which appears nearly homogeneous. The females have enamel that in parts is much thicker, giving a vertically grooved appearance to the teeth. Wide variation in the involvement in females is also consistent with the Lyon hypothesis.

Backman (1988) described the clinical manifestations of amelogenesis imperfecta in 51 families from a northern Swedish county. Two of these families, families 22 and 41, were later found to have mutations in the AMELX gene (see 300391.0002 and 300391.0001, respectively). Family 22 had 7 affected individuals in 3 generations. All 5 females had hypoplastic AI but the surface of the enamel varied greatly: in 2 it was rough and in 3 it was pitted. In all 5, some of the teeth were seemingly unaffected. The 1 male who was studied had hypoplastic AI with thin, smooth enamel. Family 41 had 17 affected individuals in 4 generations. The 5 males with permanent teeth and 1 boy with primary teeth were described as having hypomaturation AI. Some carrier females had vertically ridged teeth with alternating bands of normal and hypoplastic enamel mainly present on the anterior teeth. Mottled opaque, white areas were also present, indicating hypomineralization. The intensity and extent of enamel defect varied from tooth to tooth and also between the women.

Hu et al. (2012) described 2 families segregating X-linked amelogenesis imperfecta with a characteristic snow-capped enamel phenotype. Affected family members exhibited minor variations in their enamel, but all had a thicker layer of enamel on the cusp tips and marginal ridges relative to the lateral tooth surfaces.


Schulze and Lenz (1952), Schulze (1957), and others pointed out that one form of amelogenesis imperfecta is X-linked.


In 2 large Swedish families (pedigrees 22 and 41 originally described by Backman and Holmgren, 1988) with X-linked amelogenesis imperfecta, Lagerstrom et al. (1989, 1990) mapped the locus to Xp22 by demonstrating no recombination with DXS85; maximum lod score = 4.45 at theta = 0.00.

In 2 of 3 affected families, Aldred et al. (1992) found strong evidence of linkage to an Xp22 marker; the combined maximum lod score for the 2 families was 7.30 for location of AIH1 2 cM distal to DXS16, using multipoint linkage analysis. A third family, however, showed significant evidence against linkage and a strong suggestion of linkage to DXS144E and F9 (300746) with no recombination with either of these markers. The peak lod score in multipoint linkage analysis was 2.84 at theta = 0. This was considered to place the locus, which they referred to as AIH3 (see 301201), at Xq22-q28. Aldred et al. (1992) observed that in the 2 families linked to Xp, clinical manifestations were similar in members of the same sex within each family, whereas in the third, Xq-linked family, the clinical features were more variable in affected members of each sex.

Molecular Genetics

By Southern blot analysis, Lagerstrom et al. (1991) demonstrated a deletion extending over 5 kb of the amelogenin gene (300391.0001) in males with the hypomineralization form of amelogenesis imperfecta. Carrier females were heterozygous for the molecular defect which appeared to include at least 2 exons of the gene. The extent of the deletion was verified by polymerase chain reaction (PCR) analysis. Segregation of the mutation with the disease was established in 15 members of the kindred analyzed. Lagerstrom-Fermer et al. (1995) stated that affected members of this family had enamel of normal thickness but that it was poorly mineralized and therefore softer than normal. This contrasted with the findings of thin enamel in a patient with a 9-bp deletion (300391.0003). They presented photographs contrasting the appearance of the teeth.

Kim et al. (2004) described 2 mutations (300391.0010 and 300391.0011) in the coding region of the AMELX signal peptide. These mutations are predicted to interfere with the secretion of amelogenin. Kim et al. (2004) stated that the common phenotype caused by these signal peptide mutations is enamel hypoplasia with malformed incisal edges on the anterior teeth. The enamel appears to have mineralized normally and contrasts with dentin on radiographs.

In affected members of 2 families segregating X-linked amelogenesis imperfecta with a characteristic snow-capped enamel phenotype, Hu et al. (2012) identified deletions of the entire AMELX gene and portions of the ARHGAP6 gene, i.e., the alternative ARHGAP6 promoters 1c and 1d (300391.0012) in a Turkish family and ARHGAP6 promoter 1d and exon 2 in an Eastern European family. By RT-PCR analysis, Hu et al. (2012) showed that the ARHGAP6 promoters are not active in ameloblasts, indicating that their deletion was unlikely to have affected the developing teeth in the Turkish family. The deletion of exon 2 was likely to have precluded expression of ARHGAP6 in the Eastern European family. Although ARHGAP6 was expressed in secretory stage ameloblasts and enamel organ epithelia of mice, Hu et al. (2012) concluded that the phenotype resulted from deletion of AMELX and that loss of ARHGAP6 expression did not appreciably alter the severity of the enamel defects.

Animal Model

Barron et al. (2010) described a tyr64-to-his missense mutation in the tri-tyrosyl domain of the enamel extracellular matrix protein of mouse Amelx. Affected animals had severe defects of enamel biomineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis, and formation of multicellular masses. Affected ameloblasts expressed but failed to secrete full-length amelogenin, leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Cotransfection of Ambn (601259) and mutant Amelx in a eukaryotic cell line revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wildtype Amelx, mutant Amelx, or Ambn, or cotransfected with both wildtype Amelx and Ambn. Barron et al. (2010) hypothesized that intracellular protein-protein interactions mediated via the amelogenin tri-tyrosyl motif may be a key mechanistic factor underpinning the molecular pathogenesis in this example of AI.