Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4

Abstract

Amelogenesis imperfecta (AI) is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.

Fig. 1.

Highly diverse clinical appearances of the human dentition result from AMELX g.4046delC (a, female dentition), ENAM g.8344delG (d) and KLK4 g.2142G>A mutations (g). The dentin (D) appears normal, while the enamel (E) affected by these different mutations shows varying degrees of opacity and hypoplasia as seen with light microscopy (b, AMELX;e, ENAM;h, KLK4). These different mutations also have markedly different effects that frequently disrupt the normal prismatic structure in the AMELX (c) and ENAM (f) enamel but not in the KLK4 AI enamel (i) as seen with scanning electron microscopy.

Fig. 2.

Wild-type mice (WT) typically have smooth enamel with a yellowish-brown coloration. Mice null for Amelx and Enam show a roughened surface, abnormal wear on the incisal edge and a white opaque appearance.

Fig. 3.

Scanning electron microscopy reveals the typical prismatic enamel (E) architecture in the wild-type mouse (a) and the complete loss of prisms in both the Amelx null (b) and Enam null (c) mice. Similar to humans, the dentin (D) appears structurally normal.