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Gene Review

ENAM  -  enamelin

Homo sapiens

Synonyms: ADAI, AI1C, AIH2, Enamelin
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Disease relevance of ENAM

  • The phenotype associated with the g.13185_13186insAG ENAM mutation is dose dependent such that ARAI with openbite malocclusion segregates as a recessive trait, and enamel pitting as a dominant trait [1].
  • Open bite malocclusion occurred in individuals with AI caused by mutations in the AMELX and ENAM genes even though these genes are considered to be predominantly or exclusively expressed in teeth [2].
  • In view of the present results, it is interesting that previous studies have indicated that although ameloblastoma, a non-mineralized odontogenic tumor, transcribes amelogenin mRNA, amelogenin (and enamelin) proteins are not expressed in this tissue [3].
  • In general, mutations in the human enamelin gene cause hypoplastic enamel, often with horizontal grooves, but the severity of the enamel defects is variable, even among individuals with the same mutation [4].
  • Immunohistochemically, only enamelin proteins were present in lower vertebrate (shark, bony fish, and larval amphibian) teeth and dermal denticles [5].

High impact information on ENAM

  • Enamelin (Enam) is essential for amelogenesis: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (AI) [6].
  • Enam(Rgsc521) heterozygotes showed a hypomaturation-type AI phenotype in the incisors, possibly due to haploinsufficiency of Enam [6].
  • Thus, we report here that the Enam gene is essential for amelogenesis, and that mice with different point mutations at Enam may provide good animal models to study the different clinical subtypes of AI [6].
  • In this study, we describe an ENAM mutation causing the local hypoplastic form of ADAI, a phenotype that accounts for 27% of the autosomally inherited cases in Northern Sweden [7].
  • A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2) [7].

Biological context of ENAM

  • Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects [1].
  • Homozygosity linkage studies were consistent for localisation of an AI locus in three families to the chromosome 4q region containing the ENAM gene [1].
  • Mutations were confirmed by sequence analysis of PCR amplified products of all 10 exons and exon/intron boundaries of the ENAM gene [8].
  • Here we review how enamelin was discovered, what is known about enamelin protein structure, post-translational modifications, processing by proteases, and its potentially important functional properties such as its affinity for hydroxyapatite and influence on crystal growth in vitro [9].
  • These results support a possible correlation between hypoplastic AI and mutations in the ENAM gene; however, identification of additional mutations could be helpful in establishing phenotype/genotype relationships [10].

Anatomical context of ENAM

  • The discovery of mutations in the ENAM gene in AI kindreds proved that enamelin is critical for proper dental enamel formation and that it plays a role in human disease [9].
  • Enamelin is a large enamel matrix protein secreted by ameloblasts [11].
  • Chromosomal mapping was performed by polymerase chain reaction (PCR) amplification using somatic hybrid and deletion/derivation cell line panels with an enamelin primer set based on 100% conserved regions between pig and mouse cDNAs [11].
  • PCR amplification using a somatic cell hybrid panel placed enamelin on chromosome 4 with analysis of a regional chromosome 4 mapping panel refining the localization to 4q 13.1-q21.23 [11].
  • The organic matrix is highly heterogeneous, comprising proteins derived from a number of different genes, including amelogenin, enamelin, ameloblastin (amelin/sheathlin), tuftelin, dentine sialophosphoprotein, enzymes and serum proteins such as albumin [12].

Associations of ENAM with chemical compounds

  • In the pig, enamelin is secreted as 186-kDa phosphorylated glycoprotein, which is rapidly processed by enamel proteinases into smaller cleavage products [13].
  • The major, non-amelogenin protein component (enamelin) present in EDTA or EDTA-GU HCl extracts of developing bovine enamel has a molecular weight of approximately 67 kD and an amino acid composition rich in asp, glu, ala, leuc and lys [14].
  • Amelogenin, enamelin, laminin, heparan sulfate proteoglycan, fibronectin, collagen type IV and type V were immunolocalized within the luminal space and along the inner rim of duct-like structures [15].

Enzymatic interactions of ENAM


Other interactions of ENAM

  • Although X-linked, autosomal dominant and autosomal recessive forms of AI have been clinically characterized, only two genes (AMELX and ENAM) have been associated with AI [17].
  • The human AMBN and ENAM genes are located on chromosome 4q13 [9].
  • How do enamelysin and kallikrein 4 process the 32-kDa enamelin [16]?
  • After 12 h of digestion with KLK4, all of the 32-kDa enamelin had been cleaved, but some cleavage products persisted after 48 h of digestion [16].
  • This paper reviews the primary structure, characteristics and possible function of tuftelin/enamelin protein [18].

Analytical, diagnostic and therapeutic context of ENAM

  • ENAM sequence analysis in families identified a 2 bp insertion mutation that introduced a premature stop codon in exon 10 [1].
  • DESIGN: In this paper, we describe the phenotype and ultrastructure of enamel observed using scanning electron microscopy (SEM) in patients with two autosomal dominant (AD) mutations in the ENAM gene: g.13185-13186insAG and g.8344delG, each in one of two unrelated families [8].
  • Then, the 32-kDa enamelin digestion products were fractionated by reverse-phase high-performance liquid chromatography (RP-HPLC) and characterized by Edman sequencing, amino acid analysis, and mass spectrometry [16].
  • Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development [13].
  • We have cloned and characterized a full-length human enamelin cDNA and determined by radiation hybrid mapping and fluorescent in situ hybridization (FISH) that the gene is located on chromosome 4q near the ameloblastin gene in a region previously linked to local hypoplastic AI in six families [13].


  1. Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects. Hart, T.C., Hart, P.S., Gorry, M.C., Michalec, M.D., Ryu, O.H., Uygur, C., Ozdemir, D., Firatli, S., Aren, G., Firatli, E. J. Med. Genet. (2003) [Pubmed]
  2. Variation in dental and skeletal open bite malocclusion in humans with amelogenesis imperfecta. Ravassipour, D.B., Powell, C.M., Phillips, C.L., Hart, P.S., Hart, T.C., Boyd, C., Wright, J.T. Arch. Oral Biol. (2005) [Pubmed]
  3. Tuftelin mRNA is expressed in a human ameloblastoma tumor. Deutsch, D., Fermon, E., Lustmann, J., Dafni, L., Mao, Z., Leytin, V., Palmon, A. Connect. Tissue Res. (1998) [Pubmed]
  4. ENAM mutations in autosomal-dominant amelogenesis imperfecta. Kim, J.W., Seymen, F., Lin, B.P., Kiziltan, B., Gencay, K., Simmer, J.P., Hu, J.C. J. Dent. Res. (2005) [Pubmed]
  5. Phylogenetic distribution of enamel proteins: immunohistochemical localization with monoclonal antibodies indicates the evolutionary appearance of enamelins prior to amelogenins. Herold, R., Rosenbloom, J., Granovsky, M. Calcif. Tissue Int. (1989) [Pubmed]
  6. Enamelin (Enam) is essential for amelogenesis: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (AI). Masuya, H., Shimizu, K., Sezutsu, H., Sakuraba, Y., Nagano, J., Shimizu, A., Fujimoto, N., Kawai, A., Miura, I., Kaneda, H., Kobayashi, K., Ishijima, J., Maeda, T., Gondo, Y., Noda, T., Wakana, S., Shiroishi, T. Hum. Mol. Genet. (2005) [Pubmed]
  7. A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2). Mårdh, C.K., Bäckman, B., Holmgren, G., Hu, J.C., Simmer, J.P., Forsman-Semb, K. Hum. Mol. Genet. (2002) [Pubmed]
  8. Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG. Pavlic, A., Petelin, M., Battelino, T. Arch. Oral Biol. (2007) [Pubmed]
  9. Enamelin and autosomal-dominant amelogenesis imperfecta. Hu, J.C., Yamakoshi, Y. Crit. Rev. Oral Biol. Med. (2003) [Pubmed]
  10. Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta. Gutierrez, S.J., Chaves, M., Torres, D.M., Briceño, I. Arch. Oral Biol. (2007) [Pubmed]
  11. Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus. Dong, J., Gu, T.T., Simmons, D., MacDougall, M. Eur. J. Oral Sci. (2000) [Pubmed]
  12. The developing enamel matrix: nature and function. Robinson, C., Brookes, S.J., Shore, R.C., Kirkham, J. Eur. J. Oral Sci. (1998) [Pubmed]
  13. Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development. Hu, C.C., Hart, T.C., Dupont, B.R., Chen, J.J., Sun, X., Qian, Q., Zhang, C.H., Jiang, H., Mattern, V.L., Wright, J.T., Simmer, J.P. J. Dent. Res. (2000) [Pubmed]
  14. Major "enamelin" protein in enamel of developing bovine teeth is albumin. Strawich, E., Glimcher, M.J. Connect. Tissue Res. (1989) [Pubmed]
  15. Enamel proteins and extracellular matrix molecules are co-localized in the pseudocystic stromal space of adenomatoid odontogenic tumor. Murata, M., Cheng, J., Horino, K., Hara, K., Shimokawa, H., Saku, T. J. Oral Pathol. Med. (2000) [Pubmed]
  16. How do enamelysin and kallikrein 4 process the 32-kDa enamelin? Yamakoshi, Y., Hu, J.C., Fukae, M., Yamakoshi, F., Simmer, J.P. Eur. J. Oral Sci. (2006) [Pubmed]
  17. Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature. Hart, P.S., Michalec, M.D., Seow, W.K., Hart, T.C., Wright, J.T. Arch. Oral Biol. (2003) [Pubmed]
  18. The enamelin (tuftelin) gene. Deutsch, D., Palmon, A., Dafni, L., Catalano-Sherman, J., Young, M.F., Fisher, L.W. Int. J. Dev. Biol. (1995) [Pubmed]
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