AMBN

Summary

AMBN (ameloblastin, HGNC:452) is a protein-coding gene on chromosome 4q13.3, encoding Ameloblastin (Q9NP70). Involved in the mineralization and structural organization of enamel.

This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfect and autosomal dominant amylogenesis imperfect.

Source: NCBI Gene 258 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta type 1F (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 99 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_016519

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:452
Approved symbol	AMBN
Name	ameloblastin
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000178522
Ensembl biotype	protein_coding
OMIM	601259
Entrez	258

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000322937, ENST00000449493

RefSeq mRNA: 1 — MANE Select: NM_016519 NM_016519

CCDS: CCDS3543

Canonical transcript exons

ENST00000322937 — 13 exons

Exon	Start	End
ENSE00001264291	70601418	70601654
ENSE00001264299	70599536	70599646
ENSE00001264306	70598356	70598403
ENSE00001264314	70596999	70597049
ENSE00001332138	70593327	70593395
ENSE00001365763	70603260	70603319
ENSE00001370813	70603877	70603921
ENSE00001371888	70603416	70603460
ENSE00001838737	70592256	70592373
ENSE00001935357	70606185	70607288
ENSE00002502393	70602972	70603010
ENSE00002513079	70602624	70602662
ENSE00002528837	70602798	70602836

Expression profiles

Bgee: expression breadth broad, 32 present calls, max score 91.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5103 / max 226.2252, expressed in 75 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47985	0.2779	52
47987	0.2094	30
47986	0.0230	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.03	gold quality
periodontal ligament	UBERON:0008266	71.12	silver quality
diaphragm	UBERON:0001103	68.67	gold quality
type B pancreatic cell	CL:0000169	67.66	gold quality
olfactory bulb	UBERON:0002264	64.98	gold quality
putamen	UBERON:0001874	64.84	gold quality
buccal mucosa cell	CL:0002336	64.59	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.05	gold quality
gingival epithelium	UBERON:0001949	61.71	gold quality
caudate nucleus	UBERON:0001873	60.64	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	60.57	gold quality
male germ cell	CL:0000015	59.93	gold quality
endothelial cell	CL:0000115	59.65	gold quality
sperm	CL:0000019	59.11	gold quality
epithelium of nasopharynx	UBERON:0001951	58.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.51	gold quality
superficial temporal artery	UBERON:0001614	58.25	gold quality
lateral globus pallidus	UBERON:0002476	57.35	gold quality
gluteal muscle	UBERON:0002000	57.17	gold quality
thymus	UBERON:0002370	56.91	gold quality
subthalamic nucleus	UBERON:0001906	56.88	gold quality
decidua	UBERON:0002450	56.55	gold quality
dorsal plus ventral thalamus	UBERON:0001897	56.48	gold quality
ventral tegmental area	UBERON:0002691	56.30	gold quality
inferior vagus X ganglion	UBERON:0005363	56.28	gold quality
amniotic fluid	UBERON:0000173	55.83	gold quality
saphenous vein	UBERON:0007318	55.75	gold quality
gingiva	UBERON:0001828	55.74	gold quality
trigeminal ganglion	UBERON:0001675	55.69	gold quality
synovial joint	UBERON:0002217	55.49	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.42
E-GEOD-75140	no	114.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX2

miRNA regulators (miRDB)

44 targeting AMBN, 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-3646	100.00	73.56	5283
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-633	98.35	69.45	1167

Literature-anchored findings (GeneRIF, showing 20)

• The frequently detected AMBN alterations in ameloblastomas are polymorphisms, which appear to be unrelated to the occurrence of ameloblastomas. (PMID:17331365)
• a bipolar calcium-binding molecule [with] a possible role in protein-protein interactions (PMID:18353005)
• Mutation of ameloblastin gene is associated with calcifying epithelial odontogenic tumor. (PMID:19661317)
• The identification of a fibronectin-binding domain in ameloblastin might permit interesting applications for dental implantology. (PMID:20043904)
• found to induce, directly and indirectly, signal transducer and activator of transcription (STAT) 1 and 2 and downstream factors in the interferon pathway (PMID:20831578)
• Findings suggest a role for this protein in early bone formation and repair. (PMID:20854943)
• ameloblastin is expressed in osteoblasts and functions as a promoting factor for osteogenic differentiation via a novel pathway through the interaction between CD63 and integrin beta1 (PMID:21149578)
• AMBN does not influence osteogenic activity in vitro under the conditions used (PMID:21761392)
• AMBN ribbons exhibited lengths ranging from tens to hundreds of nm. Deletion analysis and NMR spectroscopy revealed that N-terminal segment encoded by exon 5 comprises two short independently structured regions and plays a role in self-assembly of AMBN (PMID:23782691)
• We found a trend for association between variation in AMBN and MIH in both cohorts, which may suggest that variation in the regulation of AMBN is a mechanism that leads to MIH. (PMID:23790503)
• Association between caries experience (caries-free versus caries affected) depending on asthma status and SNPs was tested. Logistic regression showed an association between AMBN rs4694075 and caries experience. Ameloblastin is associated w/caries in asthmatic children. (PMID:24203249)
• Report shows for the first time that AMBN mutations cause non-syndromic human amelogenesis imperfecta and confirms that mouse models with disrupted Ambn function are valid. (PMID:24858907)
• two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. (PMID:25373699)
• Protein interaction between Ambn and Psma3 can facilitate redistribution of ameloblastin domains within forming enamel. (PMID:26070558)
• Authors perform an evolutionary analysis of mammalian AMBN sequences in order to predict functionally important sites of the protein and to identify candidate disease-associated mutations responsible for the protein function and identify AMBN as a candidate for amelogenesis imperfect in humans. (PMID:26223266)
• these results indicate that AMBN enhances IL-1beta production in LPS-treated U937 cells through ERK1/2 phosphorylation and caspase-1 activation, suggesting that AMBN upregulates the inflammatory response in human macrophages and plays an important role in innate immunity. (PMID:28295583)
• Single nucleotide polymorphisms in the AMELX and AMBN genes may be genetic variants that contribute to developmental defects of enamel in primary dentition of Polish children. (PMID:28382465)
• the calcium level was associated with genetic variations in AMELX, AMNB and ESRRB. AMELX and AMNB are involved in enamel mineralization. Mutations in both these genes are responsible for the amelogenesis imperfecta phenotype (OMIN), which supports their link with enamel alterations as well as enamel mineralization. (PMID:28395292)
• Ameloblastin is critical for the initiation of enamel ribbon formation, and its absence results in pathological mineralization within the enamel organ epithelia. (PMID:31402633)
• Novel Ameloblastin Variants, Contrasting Amelogenesis Imperfecta Phenotypes. (PMID:38058155)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ambn	ENSMUSG00000029288
rattus_norvegicus	Ambn	ENSRNOG00000003718

Protein

Protein identifiers

Ameloblastin — Q9NP70 (reviewed: Q9NP70)

All UniProt accessions (2): Q9NP70, Q546D7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the mineralization and structural organization of enamel.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Ameloblast-specific. Located at the Tomes processes of secretory ameloblasts and in the sheath space between rod-interrod enamel.

Disease relevance. Amelogenesis imperfecta 1F (AI1F) [MIM:616270] A form of amelogenesis imperfecta, a disorder characterized by defective enamel formation. The enamel may be hypoplastic, hypomineralized or both, and affected teeth may be discoloured, sensitive or prone to disintegration. AI1F is characterized by hypoplastic enamel of the primary and secondary dentition. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ameloblastin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NP70-1	1	yes
Q9NP70-2	2

RefSeq proteins (1): NP_057603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007798	Amelin	Family

Pfam: PF05111

UniProt features (22 total): sequence conflict 6, sequence variant 5, region of interest 3, repeat 2, modified residue 2, signal peptide 1, chain 1, splice variant 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP70-F1	44.05	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 37, 43

Glycosylation sites (1): 112

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: 103 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOMF_GROWTH_FACTOR_ACTIVITY, chr4q13, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, WTGAAAT_UNKNOWN, TGANTCA_AP1_C, GATA1_04, GOBP_ODONTOGENESIS_OF_DENTIN_CONTAINING_TOOTH, FOXJ2_02, IK3_01, GOMF_SIGNALING_RECEPTOR_BINDING, NFE2_01

GO Biological Process (5): cell adhesion (GO:0007155), biomineral tissue development (GO:0031214), regulation of cell population proliferation (GO:0042127), odontogenesis of dentin-containing tooth (GO:0042475), signal transduction (GO:0007165)

GO Molecular Function (3): growth factor activity (GO:0008083), structural constituent of tooth enamel (GO:0030345), protein binding (GO:0005515)

GO Cellular Component (2): endoplasmic reticulum lumen (GO:0005788), extracellular region (GO:0005576)

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	2
regulation of cellular process	2
tissue development	1
animal organ development	1
cell population proliferation	1
odontogenesis	1
cell communication	1
signaling	1
cellular response to stimulus	1
receptor ligand activity	1
extracellular matrix structural constituent conferring compression resistance	1
binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1315 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMBN	ENAM	Q9NRM1	999
AMBN	AMTN	Q6UX39	992
AMBN	TUFT1	Q9NNX1	992
AMBN	AMELX	Q99217	984
AMBN	MMP20	O60882	885
AMBN	DSPP	Q9NZW4	837
AMBN	KLK4	Q9Y5K2	825
AMBN	IBSP	P21815	819
AMBN	ODAM	A1E959	780
AMBN	BMP3	P12645	779
AMBN	ODAPH	Q17RF5	720
AMBN	WDR72	Q3MJ13	714
AMBN	SACK1H	Q6ZRV2	706
AMBN	ALB	P02768	691
AMBN	SPP1	P10451	684

IntAct

28 interactions, top by confidence:

A	B	Type	Score
AMBN	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
AMBN	ICAM5	psi-mi:“MI:0915”(physical association)	0.560
BAG6	AMBN	psi-mi:“MI:0915”(physical association)	0.560
KLF11	AMBN	psi-mi:“MI:0915”(physical association)	0.560
NUP58	AMBN	psi-mi:“MI:0915”(physical association)	0.560
DNAJB6	AMBN	psi-mi:“MI:0915”(physical association)	0.560
AMBN	F11R	psi-mi:“MI:0915”(physical association)	0.560
AMBN	COL26A1	psi-mi:“MI:0915”(physical association)	0.560
FAM20C	AMBN	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMBN	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
AMBN	LRP2	psi-mi:“MI:0915”(physical association)	0.400
AMBN	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): UBAC1 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), UBQLN2 (Two-hybrid), AMBN (Affinity Capture-MS), LRP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YXV3, A0A172M4N0, A2VE23, A5PL33, C7EMF5, E7EW31, F1NSM7, I3L273, O15027, O48582, O55189, O55196, O97939, P0C671, P0DV77, P14138, Q14D33, Q1XI13, Q28989, Q3B7M4, Q4R729, Q5R7U0, Q5SWP3, Q62840, Q63003, Q6E0U4, Q6H236, Q6NUN9, Q6UXA7, Q7Z2K8, Q86UU5, Q8BM15, Q8K4E0, Q8K4L6, Q8N1P7, Q8N3D4, Q96D09, Q96JG9, Q9BGL9, Q9D7G9

Diamond homologs: O55189, Q28989, Q62840, Q9NP70, Q9XSX7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FAM20C	“up-regulates activity”	AMBN	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	64
Likely benign	10
Benign	13

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
147584	GRCh38/hg38 4q13.2-13.3(chr4:68902161-70620273)x3	Pathogenic
183689	NM_016519.6(AMBN):c.294+140_531+479del	Pathogenic
2501301	NM_016519.6(AMBN):c.539dup (p.Val181fs)	Pathogenic
2685970	GRCh37/hg19 4q13.1-13.3(chr4:63684557-71480358)x3	Pathogenic
372171	NM_016519.6(AMBN):c.532-1G>C	Pathogenic
2501302	NM_016519.6(AMBN):c.76G>A (p.Ala26Thr)	Likely pathogenic
2575130	NM_016519.6(AMBN):c.295-2A>C	Likely pathogenic

SpliceAI

1320 predictions. Top by Δscore:

Variant	Effect	Δscore
4:70592369:CTAAG:C	donor_loss	1.0000
4:70592370:TAAG:T	donor_loss	1.0000
4:70592371:AAGGT:A	donor_loss	1.0000
4:70592372:AGGT:A	donor_loss	1.0000
4:70592373:GGTAA:G	donor_loss	1.0000
4:70592374:G:C	donor_loss	1.0000
4:70592375:T:A	donor_loss	1.0000
4:70596997:A:AG	acceptor_gain	1.0000
4:70596998:G:GG	acceptor_gain	1.0000
4:70599527:T:G	acceptor_gain	1.0000
4:70599534:A:AG	acceptor_gain	1.0000
4:70599535:G:GT	acceptor_gain	1.0000
4:70599535:GT:G	acceptor_gain	1.0000
4:70599535:GTA:G	acceptor_gain	1.0000
4:70599644:CAGGT:C	donor_loss	1.0000
4:70599646:GGTG:G	donor_loss	1.0000
4:70599647:G:GA	donor_loss	1.0000
4:70601412:CTGCA:C	acceptor_loss	1.0000
4:70601413:TGCAG:T	acceptor_loss	1.0000
4:70601414:GCA:G	acceptor_loss	1.0000
4:70601415:CA:C	acceptor_loss	1.0000
4:70601416:A:AG	acceptor_gain	1.0000
4:70601416:AGTA:A	acceptor_loss	1.0000
4:70601416:AGTAT:A	acceptor_gain	1.0000
4:70601417:G:GG	acceptor_gain	1.0000
4:70601417:GT:G	acceptor_gain	1.0000
4:70601417:GTAT:G	acceptor_gain	1.0000
4:70601417:GTATG:G	acceptor_gain	1.0000
4:70601592:G:GT	donor_gain	1.0000
4:70601635:A:G	donor_gain	1.0000

AlphaMissense

2924 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:70603904:A:C	S261R	0.974
4:70603906:T:A	S261R	0.974
4:70603906:T:G	S261R	0.974
4:70597041:A:C	S43R	0.955
4:70597043:C:A	S43R	0.955
4:70597043:C:G	S43R	0.955
4:70597035:A:C	S41R	0.954
4:70597037:T:A	S41R	0.954
4:70597037:T:G	S41R	0.954
4:70601424:T:C	Y101H	0.952
4:70601425:A:G	Y101C	0.946
4:70597048:A:T	E45V	0.939
4:70597042:G:T	S43I	0.930
4:70606290:T:C	F302L	0.923
4:70606292:C:A	F302L	0.923
4:70606292:C:G	F302L	0.923
4:70599577:G:C	W75C	0.920
4:70599577:G:T	W75C	0.920
4:70601419:A:G	Y99C	0.918
4:70599575:T:A	W75R	0.907
4:70599575:T:C	W75R	0.907
4:70603911:A:T	E263V	0.902
4:70601422:A:T	E100V	0.897
4:70601425:A:C	Y101S	0.896
4:70601418:T:C	Y99H	0.885
4:70603905:G:T	S261I	0.884
4:70601419:A:C	Y99S	0.879
4:70601424:T:G	Y101D	0.878
4:70598361:G:A	M47I	0.876
4:70598361:G:C	M47I	0.876

dbSNP variants (sampled 300 via entrez): RS1000390188 (4:70600054 C>A,T), RS1000520596 (4:70604621 A>G), RS1000738119 (4:70594112 T>G), RS1001276730 (4:70605822 C>G,T), RS1001452441 (4:70593726 G>A,T), RS1001657845 (4:70599397 C>A,T), RS1001865992 (4:70601376 T>C,G), RS1001897264 (4:70601670 T>G), RS1002059383 (4:70607132 C>A), RS1002430045 (4:70606882 G>A,T), RS1002530057 (4:70604181 A>G), RS1002561301 (4:70604525 G>A), RS1002627150 (4:70598156 T>A), RS1002921853 (4:70598090 T>C), RS1002948638 (4:70604510 C>A)

Disease associations

OMIM: gene MIM:601259 | disease phenotypes: MIM:616270

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta type 1F	Strong	Autosomal recessive
amelogenesis imperfecta type 1	Supportive	Autosomal dominant

Mondo (2): amelogenesis imperfecta type 1F (MONDO:0014560), amelogenesis imperfecta type 1 (MONDO:0015047)

Orphanet (1): Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000705	Amelogenesis imperfecta
HP:0003593	Infantile onset
HP:0006297	Enamel hypoplasia
HP:0009722	Dental enamel pits
HP:0011073	Abnormality of dental color

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	increases expression	1
ferrous chloride	increases expression	1
Benzo(a)pyrene	increases methylation	1
Valproic Acid	affects expression	1
Zinc	decreases expression	1
Acrylamide	decreases expression	1
S-Nitrosoglutathione	increases expression	1

Clinical trials (associated diseases)

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