Human and Mouse Enamel Phenotypes Resulting from Mutation or Altered Expression of <i>AMEL, ENAM</i>, <i>MMP20</i> and <i>KLK4</i>

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.

The Amelogenin Proteins and Enamel Development in Humans and Mice

“…Mouse models for AI have been developed to test the function of the amelogenin protein group, and to begin to define the roles of the individual amelogenin proteins. Mice have been generated to express an overabundance of one amelogenin, to express a mutated amelogenin or to express only one amelogenin, but none of the other amelogenins 24,25,26 .…”

Amelogenin gene influence on enamel defects of cleft lip and palate patients

“…Mutations in enamel proteins and protease genes have been associated with ED. 3,23,24,25,26 The cause of ED could be a n=number; ()=total per group; homo=homozygous mutation; hetero=heterozygous mutation; * means amino acid substitution genetic disorder linked to specific and nonspecific diseases during odontogenesis with the mineral metabolism, especially calcium phosphate. Some researchers suggest that CLP could be related to these enamel alterations, in which case a direct relationship would exist between defect appearance and cleft presence.…”

“…Some researchers suggest that CLP could be related to these enamel alterations, in which case a direct relationship would exist between defect appearance and cleft presence. 16,17 Considering that ED could be related to different mutations located in several genes involved in tooth enamel formation, and that the amelogenin gene forms the skeleton for the mineralization and the formation of the enamel crystals, 3 the investigation of genes that transcribe the main proteins and proteases of enamel is essential to gaining a better understanding of these alterations. AMELX is composed of seven exons and six introns, and alternative splicing results in three different transcripts, according to Ensembl.…”

“…The authors asserted that ED is poorly understood and that many studies regarding genes in human tooth development are significantly limited. 3 Thus, since AMELX encodes a protein that plays a key role in the organization and structure of the enamel, it is the key player for organizing and structuring this highly mineralized tissue. 30 Another study reported two SNPs in the AMELX coding sequences in humans.…”

“…: amelogenin (AMELX), enamelin (ENAM), kallikrein-4 (KLK-4), matrix metalloprotease-20 (MMP-20), ameloblastin 3 and more recently DLX3, 4 FAM83H, 5,6,7 WDR72 5 and SLC4A4. 8 AMELX encodes a member of the amelogenin family of extracellular matrix protein and has an important role in biomineralization during tooth enamel development.…”