AMTN

Summary

AMTN (amelotin, HGNC:33188) is a protein-coding gene on chromosome 4q13.3, encoding Amelotin (Q6UX39). Is a promoter of calcium phosphate mineralization, playing a critical role in the formation of the compact, mineralized, aprismatic enamel surface layer during the maturation stage of amelogenesis.

The mineralized portions of teeth, the dentin and enamel, are formed by mesenchyme-derived odontoblasts and epithelium-derived ameloblasts, respectively. As ameloblasts differentiate, they deposit specific proteins necessary for enamel formation, including amelogenin (AMELX; MIM 300391), enamelin (ENAM; MIM 606585), and ameloblastin (AMBN; MIM 601259), in the organic enamel matrix. Amelotin is specifically expressed in maturation-stage ameloblasts (Iwasaki et al., 2005 [PubMed 16304441]).

Source: NCBI Gene 401138 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta, type 3A (Supportive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 37 total — 2 pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_212557

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33188
Approved symbol	AMTN
Name	amelotin
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	UNQ689, RSTI689
Ensembl gene	ENSG00000187689
Ensembl biotype	protein_coding
OMIM	610912
Entrez	401138

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000339336, ENST00000504451

RefSeq mRNA: 2 — MANE Select: NM_212557 NM_001286731, NM_212557

CCDS: CCDS3542, CCDS68716

Canonical transcript exons

ENST00000339336 — 9 exons

Exon	Start	End
ENSE00001364328	70518569	70518654
ENSE00001365873	70522755	70522838
ENSE00001366769	70531039	70531300
ENSE00001368789	70532455	70532743
ENSE00001377119	70523868	70523933
ENSE00001385611	70524872	70524961
ENSE00001389852	70518763	70518831
ENSE00001391230	70528723	70528758
ENSE00001391726	70529184	70529210

Expression profiles

Bgee: expression breadth broad, 38 present calls, max score 67.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.5075 / max 607.8789, expressed in 116 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47982	1.0612	104
47983	0.3724	79
47981	0.0738	25

Top tissues by expression

127 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tonsil	UBERON:0002372	67.50	gold quality
minor salivary gland	UBERON:0001830	66.40	gold quality
saliva-secreting gland	UBERON:0001044	65.72	gold quality
lower esophagus mucosa	UBERON:0035834	60.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	59.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	48.75	silver quality
prostate gland	UBERON:0002367	46.41	gold quality
esophagus mucosa	UBERON:0002469	43.93	gold quality
fundus of stomach	UBERON:0001160	42.92	gold quality
mucosa of stomach	UBERON:0001199	42.84	silver quality
sural nerve	UBERON:0015488	41.70	gold quality
right lung	UBERON:0002167	40.98	gold quality
bone marrow cell	CL:0002092	38.36	gold quality
stomach	UBERON:0000945	38.30	gold quality
body of stomach	UBERON:0001161	37.91	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
muscle tissue	UBERON:0002385	35.61	silver quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	35.05	gold quality
bone marrow	UBERON:0002371	34.26	gold quality
zone of skin	UBERON:0000014	33.29	gold quality
esophagus	UBERON:0001043	33.21	gold quality
skin of leg	UBERON:0001511	33.21	gold quality
skin of abdomen	UBERON:0001416	33.19	gold quality
lung	UBERON:0002048	32.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
islet of Langerhans	UBERON:0000006	32.02	silver quality
upper lobe of left lung	UBERON:0008952	31.37	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	1224.13
E-ANND-3	yes	3.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP6

miRNA regulators (miRDB)

17 targeting AMTN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-4259	95.68	65.25	582

Literature-anchored findings (GeneRIF, showing 6)

• proinflammatory cytokines induce Amelotin gene transcription and a role for Amelotin in gingival inflammation (PMID:25158173)
• AMTN has a direct influence on biomineralization by promoting hydroxyapatite mineralization. (PMID:25407797)
• Results show that AMTN and KLK4 are not essential for biological processes outside of the dentition or during the secretory stage of amelogenesis. Both KLK4 and AMTN proved to be essential for the maturation of dental enamel, a process that requires the removal of extracellularmatrix proteins and the deposition of ions on the sides of enamel crystallites. (PMID:26620968)
• This study demonstrates for the first time that AMTN mutations cause non-syndromic human Amelogenesis imperfecta (AI) and explores the human phenotype, comparing it with that of mice with disrupted Amtn function. (PMID:27412008)
• TNF-alpha stimulates AMTN gene transcription in human gingival epithelial cells via C/EBP1, C/EBP2, and YY1 elements in the human AMTN gene promoter. (PMID:29282478)
• Amelotin is expressed in retinal pigment epithelium and localizes to hydroxyapatite deposits in dry age-related macular degeneration. (PMID:32160961)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Amtn	ENSMUSG00000029282
rattus_norvegicus	Amtn	ENSRNOG00000003776

Protein

Protein identifiers

Amelotin — Q6UX39 (reviewed: Q6UX39)

All UniProt accessions (2): F1T0L8, Q6UX39

UniProt curated annotations — full annotation on UniProt →

Function. Is a promoter of calcium phosphate mineralization, playing a critical role in the formation of the compact, mineralized, aprismatic enamel surface layer during the maturation stage of amelogenesis.

Subcellular location. Secreted.

Post-translational modifications. Phosphorylated by FAM20C in vitro. O-glycosylated.

Disease relevance. Amelogenesis imperfecta 3B (AI3B) [MIM:617607] An autosomal dominant form of amelogenesis imperfecta, a defect of enamel formation. AI3B is characterized by hypomineralized enamel that has reduced tickness and exhibits structural defects. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the amelotin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UX39-1	1	yes
Q6UX39-2	2

RefSeq proteins (2): NP_001273660, NP_997722* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031501	Amelotin	Family

Pfam: PF15757

UniProt features (7 total): sequence variant 3, signal peptide 1, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX39-F1	48.75	0.00

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 69 (showing top): GOBP_TOOTH_MINERALIZATION, CEBPB_01, chr4q13, CEBP_Q2, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_ENAMEL_MINERALIZATION, WTGAAAT_UNKNOWN, IRF_Q6, GOBP_AMELOGENESIS, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, GOCC_BASEMENT_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOCC_CELL_CELL_JUNCTION, GOBP_ODONTOGENESIS, GOCC_ENDOPLASMIC_RETICULUM_LUMEN

GO Biological Process (5): cell adhesion (GO:0007155), biomineral tissue development (GO:0031214), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of biomineral tissue development (GO:0070169), positive regulation of enamel mineralization (GO:0070175)

GO Molecular Function (2): molecular_function (GO:0003674), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), basement membrane (GO:0005604), endoplasmic reticulum lumen (GO:0005788), cell-cell junction (GO:0005911), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	2
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
tissue development	1
animal organ development	1
odontogenesis	1
biomineral tissue development	1
positive regulation of developmental process	1
regulation of biomineral tissue development	1
enamel mineralization	1
positive regulation of tooth mineralization	1
regulation of enamel mineralization	1
binding	1
cellular anatomical structure	1
extracellular matrix	1
endoplasmic reticulum	1
intracellular organelle lumen	1
anchoring junction	1
external encapsulating structure	1

Protein interactions and networks

STRING

462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMTN	ENAM	Q9NRM1	993
AMTN	AMBN	Q9NP70	992
AMTN	ODAM	A1E959	963
AMTN	AMELX	Q99217	934
AMTN	MMP20	O60882	782
AMTN	KLK4	Q9Y5K2	763
AMTN	ODAPH	Q17RF5	720
AMTN	ACP4	Q9BZG2	687
AMTN	WDR72	Q3MJ13	660
AMTN	COL17A1	Q9UMD9	650
AMTN	SACK1H	Q6ZRV2	641
AMTN	TUFT1	Q9NNX1	630
AMTN	DMP1	Q13316	627
AMTN	LAMB3	Q13751	621
AMTN	DLX3	O60479	613

IntAct

9 interactions, top by confidence:

A	B	Type	Score
BAG6	AMTN	psi-mi:“MI:0915”(physical association)	0.560
FAM20C	AMTN	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMTN	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMTN	NARS1	psi-mi:“MI:0914”(association)	0.350
AMTN	SERPINF1	psi-mi:“MI:0914”(association)	0.350
AMTN	SERPINB7	psi-mi:“MI:0914”(association)	0.350

BioGRID (26): LRRC40 (Affinity Capture-MS), SEC24D (Affinity Capture-MS), PTPN1 (Affinity Capture-MS), RABL6 (Affinity Capture-MS), NARS (Affinity Capture-MS), CYB5R3 (Affinity Capture-MS), PPID (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), GINS4 (Affinity Capture-MS), BAG6 (Two-hybrid), CLCC1 (Affinity Capture-MS), LRRC40 (Affinity Capture-MS), SERPINF1 (Affinity Capture-MS), PPID (Affinity Capture-MS), TGM3 (Affinity Capture-MS)

ESM2 similar proteins: A1E959, A1E960, A1YQ91, A1YQ92, A1YQ93, A1YQ94, B3A0S0, B5DRT7, O55189, O62823, P02661, P02662, P02665, P02668, P02669, P02670, P04653, P06796, P10598, P11840, P11841, P18626, P19228, P19442, P33618, P39035, P39037, P42155, P42156, P42157, P50420, P50421, P50422, P50423, P50424, P50425, P63277, P63278, Q003G9, Q27002

Diamond homologs: Q3HS82, Q6UX39, Q9D3J8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

37 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	22
Likely benign	3
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
155391	GRCh38/hg38 4q13.2-22.3(chr4:68686088-95294456)x3	Pathogenic
431413	NM_212557.4(AMTN):c.54+1348_330+98delinsCTCA	Pathogenic

SpliceAI

867 predictions. Top by Δscore:

Variant	Effect	Δscore
4:70523931:CTGG:C	donor_loss	1.0000
4:70523933:GGT:G	donor_loss	1.0000
4:70523934:G:GG	donor_gain	1.0000
4:70523934:GTA:G	donor_loss	1.0000
4:70523935:T:G	donor_loss	1.0000
4:70524870:A:AG	acceptor_gain	1.0000
4:70524871:G:GG	acceptor_gain	1.0000
4:70531032:A:AG	acceptor_gain	1.0000
4:70531038:GCCAC:G	acceptor_gain	1.0000
4:70518829:CCA:C	donor_gain	0.9900
4:70518830:CA:C	donor_gain	0.9900
4:70518830:CAGTA:C	donor_loss	0.9900
4:70518831:AGT:A	donor_loss	0.9900
4:70518832:G:T	donor_loss	0.9900
4:70518832:GTAA:G	donor_gain	0.9900
4:70518833:T:G	donor_loss	0.9900
4:70522748:A:AG	acceptor_gain	0.9900
4:70522749:C:G	acceptor_gain	0.9900
4:70522750:A:AG	acceptor_gain	0.9900
4:70523862:CTGCA:C	acceptor_loss	0.9900
4:70523864:GC:G	acceptor_loss	0.9900
4:70523865:CA:C	acceptor_loss	0.9900
4:70523867:G:T	acceptor_loss	0.9900
4:70523936:AA:A	donor_loss	0.9900
4:70524871:GTT:G	acceptor_gain	0.9900
4:70524871:GTTA:G	acceptor_gain	0.9900
4:70524871:GTTAA:G	acceptor_gain	0.9900
4:70531035:CCA:C	acceptor_loss	0.9900
4:70531036:CAGC:C	acceptor_loss	0.9900
4:70531037:A:AG	acceptor_gain	0.9900

AlphaMissense

1321 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:70529196:A:C	S115R	0.947
4:70529198:C:A	S115R	0.947
4:70529198:C:G	S115R	0.947
4:70528739:T:A	V104D	0.886
4:70529203:A:T	E117V	0.867
4:70529197:G:T	S115I	0.827
4:70523890:T:C	I54T	0.812
4:70528733:T:C	I102T	0.809
4:70518802:T:C	C9R	0.800
4:70528730:C:G	P101R	0.799
4:70528733:T:A	I102N	0.781
4:70528730:C:T	P101L	0.779
4:70528733:T:G	I102S	0.761
4:70528735:T:C	F103L	0.751
4:70528737:T:A	F103L	0.751
4:70528737:T:G	F103L	0.751
4:70531054:A:C	S125R	0.750
4:70531056:C:A	S125R	0.750
4:70531056:C:G	S125R	0.750
4:70529209:T:C	L119S	0.746
4:70523890:T:A	I54K	0.740
4:70523871:T:C	F48L	0.728
4:70523873:T:A	F48L	0.728
4:70523873:T:G	F48L	0.728
4:70529206:A:T	E118V	0.728
4:70531048:T:C	F123L	0.728
4:70531050:C:A	F123L	0.728
4:70531050:C:G	F123L	0.728
4:70531049:T:C	F123S	0.725
4:70528730:C:A	P101Q	0.724

dbSNP variants (sampled 300 via entrez): RS1000205647 (4:70525986 T>A,C), RS1000429309 (4:70520420 C>G), RS1000440233 (4:70526329 A>G), RS1000488832 (4:70524692 C>G,T), RS1000641520 (4:70530710 C>G,T), RS1000712696 (4:70531947 T>C), RS1001174845 (4:70519311 C>G), RS1001246584 (4:70529096 ATTTTAAG>A), RS1001524251 (4:70532215 C>T), RS1001542495 (4:70531586 C>T), RS1001621781 (4:70520319 A>G), RS1002047394 (4:70524328 A>G,T), RS1002054612 (4:70525778 T>C,G), RS1002066862 (4:70525539 T>C,G), RS1002274771 (4:70529997 T>C)

Disease associations

OMIM: gene MIM:610912 | disease phenotypes: MIM:130900, MIM:617607

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta, type 3A	Supportive	Autosomal dominant
amelogenesis imperfecta type 3B	Limited	Autosomal dominant

Mondo (2): amelogenesis imperfecta, type 3A (MONDO:0007538), amelogenesis imperfecta type 3B (MONDO:0021547)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000705	Amelogenesis imperfecta
HP:0003593	Infantile onset
HP:0006285	Enamel hypomineralization

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562880	Amelogenesis Imperfecta, Type III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation	1
kojic acid	decreases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arbutin	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Mustard Gas	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.