Enamelin

ENAM
Identifiers
Aliases	ENAM, AIH2, AI1C, ADAI, enamelin
External IDs	OMIM: 606585; MGI: 1333772; HomoloGene: 9698; GeneCards: ENAM; OMA:ENAM - orthologs
Gene location (Human) Chr. Chromosome 4 (human) Band 4q13.3 Start 70,628,744 bp End 70,646,824 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5|5 E1 Start 88,635,834 bp End 88,653,908 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans vastus lateralis muscle striated muscle tissue biceps brachii kidney deltoid muscle corpus epididymis gallbladder gastrocnemius muscle left ventricle Top expressed in molar tracheobronchial tree intestinal villus inferior colliculus superior colliculus primary motor cortex medulla oblongata More reference expression data BioGPS n/a
Gene ontology Molecular function structural constituent of tooth enamel protein binding Cellular component extracellular region endoplasmic reticulum lumen extracellular matrix Biological process odontogenesis of dentin-containing tooth biomineral tissue development amelogenesis regulation of cell morphogenesis ameloblast differentiation positive regulation of enamel mineralization post-translational protein modification Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10117 13801 Ensembl ENSG00000132464 ENSMUSG00000029286 UniProt Q9NRM1 O55196 RefSeq (mRNA) NM_031889 NM_001368133 NM_017468 RefSeq (protein) NP_114095 NP_001355062 NP_059496 Location (UCSC) Chr 4: 70.63 – 70.65 Mb Chr 5: 88.64 – 88.65 Mb PubMed search
Wikidata
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Enamelin
Identifiers
Symbol	Enamelin
Pfam	PF15362
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Enamelin is an enamel matrix protein (EMPs), that in humans is encoded by the ENAM gene. It is part of the non-amelogenins, which comprise 10% of the total enamel matrix proteins. It is one of the key proteins thought to be involved in amelogenesis (enamel development).

Function

Dental enamel is a highly mineralized tissue with 96% of its volume occupied by unusually large, highly organised, hydroxyapatite crystals. This highly organised and unusual structure is thought to be rigorously controlled in ameloblasts through interactions of various organic matrix protein molecules that include: enamelin, amelogenin (AMELX), ameloblastin (AMBN), tuftelin (TUFT1), dentine sialophosphoprotein (DSPP), and a variety of enzymes. Enamelin is the largest protein (~168kDa) in the enamel matrix of developing teeth and is the least abundant (encompasses approximately 5%) of total enamel matrix proteins. [supplied by OMIM] It is present predominantly at the growing enamel surface.

Structure

Enamelin is thought to be the oldest member of the enamel matrix protein (EMP) family, with animal studies showing remarkable conservation of the gene phylogenetically. All other EMPs are derived from enamelin, such as amelogenin. EMPs belong to a larger family of proteins termed 'secretory calcium-binding phosphoproteins' (SCPP);

Similar to other enamel matrix proteins, enamelin undergoes extensive post-translational modifications (mainly phosphorylation), processing, and secretion by proteases. Enamelin has three putative phosphoserines (Ser⁵⁴, Ser¹⁹¹, and Ser²¹⁶ in humans) phosphorylated by a Golgi-associated secretory pathway kinase (FAM20C) based on their distinctive Ser-x-Glu (S-x-E) motifs. The major secretory product of the ENAM gene has 1103 amino acids (high in Glycine and Proline), and has an isoelectric point ranging from 4.5 to 6.5 (depending on the fragment).

The protein is involved in the mineralization and structural organization of enamel. Defects in this gene result in amelogenesis imperfect type 1C (2nd tab)

The full-length protein and its largest derivative fragments (to about 89 kDa) created as soon as the protein is secreted are not detected inside forming (secretory stage) enamel; these are present only at the growing enamel surface.

Small fragments from enamelin, however, do linger within enamel (e.g., 32 kDa and 25 kDa); these bind strongly to mineral and are inhibitory to crystal growth.

The EDTA-soluble protein described in older literature as “enamelin” turned out to be enamelin albumin derived from blood contamination - legacy protein (Nanci)

The protein is present in highest concentration at the mineralization front, but a proteolytic fragment of enamelin is located among the enamel crystals throughout the secretory stage enamel matrix. Molecular interactions between enamelin and amelogenin have been shown in in vitro experiments and very likely are important for proper enamel crystal growth. Hand and Frank

Function

Words
Believed to function in part as a modulator for de novo formation of mineral and to promote crystal elongation. Ted Cate's

Concentrated near the cell surface at sites where they are secreted (mineralisation front). At these growth sites, the interface between the membrane and the lengthening extremity of crystals can in fact be regarded as a mineralization front

Critical for enamel mineralization and adhesion of ameloblasts to enamel surface during the secretory stage. Hand and Frank

It is speculated that this protein could interact with amelogenin or other enamel matrix proteins and be important in determining growth of the length of enamel crystallites.

Binds to HAP. It is known to retard seeded growth. Anderson

Murine Studies

Words

Studies using knockout mice (which do not express a given protein), transgenic mice (overexpressing selected protein or ones with point mutations), and mutant mice (expressing altered/defective proteins) are providing us with invaluable information on the function of the various amelo- blast products. Transgenic mice expressing mutated forms of amelogenin and knockout mice exhibit major enamel struc- tural defects that affect overall thickness and enamel rod structure. Consistent with their proposed role in promoting and sustaining mineral formation, no structured enamel layer forms in mice expressing defective ameloblastin or enamelin. This is also the case when expression of enamelin is completely abrogated, attesting to the critical role of non- amelogenins. Nanci

Clinical significance

Words
Loss of function & mutant protein: No defined enamel layer. Nanci

Mutations in ENAM cause a severe form of autosomal-dominant smooth hypoplastic AI that represents 1.5%, and a mild form of autosomal-dominant local hypoplastic AI that accounts for 27% of AI cases in Sweden. (Hu and Yamakoshi)

Autosomal Dominant Hypoplastic AI - ENAM (Hand and Frank)

Mutations in the genes for enamel matrix proteins such as amelogenin (AMELX) and enamelin (ENAM) result in varying degrees of enamel hypoplasia and hypomineralization. These include pit- ting and grooves, as well as generalized thin enamel, and disruption of the normal rod structure.

Three different mutations ENAM gene mutations are associated with different AI types. Anderson

See also

Ameloblastin

Amelogenin

Amelogenesis

Amelogenesis imperfecta

Further reading

• Gutierrez SJ, Chaves M, Torres DM, Briceño I (May 2007). "Identification of a novel mutation in the enamalin gene in a family with autosomal-dominant amelogenesis imperfecta". Archives of Oral Biology. 52 (5): 503–6. doi:10.1016/j.archoralbio.2006.09.014. PMID 17316551.
• Pavlic A, Petelin M, Battelino T (March 2007). "Phenotype and enamel ultrastructure characteristics in patients with ENAM gene mutations g.13185-13186insAG and 8344delG". Archives of Oral Biology. 52 (3): 209–17. doi:10.1016/j.archoralbio.2006.10.010. PMID 17125728.
• Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP (November 2004). "Phosphoproteomic analysis of the developing mouse brain". Molecular & Cellular Proteomics. 3 (11): 1093–101. doi:10.1074/mcp.M400085-MCP200. PMID 15345747.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Hart TC, Hart PS, Gorry MC, Michalec MD, Ryu OH, Uygur C, Ozdemir D, Firatli S, Aren G, Firatli E (December 2003). "Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects". Journal of Medical Genetics. 40 (12): 900–6. doi:10.1136/jmg.40.12.900. PMC 1735344. PMID 14684688.
• Hart PS, Michalec MD, Seow WK, Hart TC, Wright JT (August 2003). "Identification of the enamelin (g.8344delG) mutation in a new kindred and presentation of a standardized ENAM nomenclature". Archives of Oral Biology. 48 (8): 589–96. doi:10.1016/S0003-9969(03)00114-6. PMID 12828988.
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Kida M, Ariga T, Shirakawa T, Oguchi H, Sakiyama Y (November 2002). "Autosomal-dominant hypoplastic form of amelogenesis imperfecta caused by an enamelin gene mutation at the exon-intron boundary". Journal of Dental Research. 81 (11): 738–42. doi:10.1177/154405910208101103. PMID 12407086.
• Rajpar MH, Harley K, Laing C, Davies RM, Dixon MJ (August 2001). "Mutation of the gene encoding the enamel-specific protein, enamelin, causes autosomal-dominant amelogenesis imperfecta". Human Molecular Genetics. 10 (16): 1673–7. doi:10.1093/hmg/10.16.1673. PMID 11487571.
• Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Dong J, Gu TT, Simmons D, MacDougall M (October 2000). "Enamelin maps to human chromosome 4q21 within the autosomal dominant amelogenesis imperfecta locus". European Journal of Oral Sciences. 108 (5): 353–8. doi:10.1034/j.1600-0722.2000.108005353.x. PMID 11037750.
• Hu CC, Hart TC, Dupont BR, Chen JJ, Sun X, Qian Q, Zhang CH, Jiang H, Mattern VL, Wright JT, Simmer JP (April 2000). "Cloning human enamelin cDNA, chromosomal localization, and analysis of expression during tooth development". Journal of Dental Research. 79 (4): 912–9. doi:10.1177/00220345000790040501. PMID 10831092.
• Forsman K, Lind L, Bäckman B, Westermark E, Holmgren G (September 1994). "Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q". Human Molecular Genetics. 3 (9): 1621–5. doi:10.1093/hmg/3.9.1621. PMID 7833920.

External links

• ENAM human gene location in the UCSC Genome Browser.
• ENAM human gene details in the UCSC Genome Browser.