ACAN

Summary

ACAN (aggrecan, HGNC:319) is a protein-coding gene on chromosome 15q26.1, encoding Aggrecan core protein (P16112). This proteoglycan is a major component of extracellular matrix of cartilagenous tissues.

This gene is a member of the aggrecan/versican proteoglycan family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage. Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration. Multiple alternatively spliced transcript variants that encode different protein isoforms have been observed in this gene.

Source: NCBI Gene 176 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ACAN-related short stature spectrum (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 96
• Clinical variants (ClinVar): 1,704 total — 136 pathogenic, 68 likely-pathogenic
• Phenotypes (HPO): 48
• MANE Select transcript: NM_001369268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:319
Approved symbol	ACAN
Name	aggrecan
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	CSPGCP
Ensembl gene	ENSG00000157766
Ensembl biotype	protein_coding
OMIM	155760
Entrez	176

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000352105, ENST00000439576, ENST00000558207, ENST00000558604, ENST00000558704, ENST00000559004, ENST00000560601, ENST00000561243

RefSeq mRNA: 5 — MANE Select: NM_001369268 NM_001135, NM_001369268, NM_001411096, NM_001411097, NM_013227

CCDS: CCDS53970, CCDS53971, CCDS92054, CCDS92055, CCDS92056

Canonical transcript exons

ENST00000560601 — 19 exons

Exon	Start	End
ENSE00000943618	88838663	88839046
ENSE00000943619	88840012	88840186
ENSE00001106198	88849438	88849731
ENSE00001106201	88845505	88845882
ENSE00001106204	88843355	88843648
ENSE00001106220	88851794	88852033
ENSE00001106229	88847911	88848038
ENSE00001106241	88847243	88847417
ENSE00001106248	88841740	88841867
ENSE00001239696	88836200	88836276
ENSE00001298612	88860326	88860439
ENSE00001365067	88872003	88872085
ENSE00001368616	88871382	88871540
ENSE00001370207	88873842	88874024
ENSE00001692879	88854852	88859417
ENSE00002462883	88872881	88873025
ENSE00002546803	88868216	88868329
ENSE00003825614	88874405	88875353
ENSE00003897909	88803436	88803809

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 99.77.

FANTOM5 (CAGE): breadth broad, TPM avg 10.1129 / max 2743.8795, expressed in 440 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148304	5.5341	237
148306	3.1288	309
148307	0.8420	179
207639	0.3009	95
148305	0.2874	86
148309	0.0198	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.77	gold quality
cartilage tissue	UBERON:0002418	99.72	gold quality
descending thoracic aorta	UBERON:0002345	95.63	gold quality
popliteal artery	UBERON:0002250	92.02	gold quality
tibial artery	UBERON:0007610	92.02	gold quality
aorta	UBERON:0000947	91.05	gold quality
tendon of biceps brachii	UBERON:0008188	90.78	gold quality
thoracic aorta	UBERON:0001515	89.95	gold quality
ascending aorta	UBERON:0001496	89.52	gold quality
middle frontal gyrus	UBERON:0002702	86.93	silver quality
trachea	UBERON:0003126	85.88	gold quality
calcaneal tendon	UBERON:0003701	85.23	gold quality
type B pancreatic cell	CL:0000169	84.92	gold quality
buccal mucosa cell	CL:0002336	84.83	gold quality
olfactory bulb	UBERON:0002264	84.60	gold quality
tendon	UBERON:0000043	83.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.35	gold quality
right coronary artery	UBERON:0001625	81.12	gold quality
periodontal ligament	UBERON:0008266	81.05	gold quality
trabecular bone tissue	UBERON:0002483	80.48	gold quality
endometrium epithelium	UBERON:0004811	79.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.00	gold quality
blood vessel layer	UBERON:0004797	76.79	gold quality
pancreatic ductal cell	CL:0002079	75.48	silver quality
Brodmann (1909) area 10	UBERON:0013541	75.30	gold quality
coronary artery	UBERON:0001621	75.16	gold quality
thymus	UBERON:0002370	74.98	gold quality
left coronary artery	UBERON:0001626	74.80	gold quality
lateral globus pallidus	UBERON:0002476	73.95	silver quality
diaphragm	UBERON:0001103	73.89	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	74.40
E-CURD-112	yes	8.28
E-ANND-3	no	5.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, HAND2, HEY1, HIF1A, MAFB, NFAT5, RARG, RUNX2, RUNX3, SCX, SHOX2, SHOX, SIRT1, SMAD2, SNAI1, SNAI2, SOX17, SOX5, SOX6, SOX9, SP1, SPI1, TCF3, TFAP2A, TWIST1, ZNF219

miRNA regulators (miRDB)

55 targeting ACAN, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-5004-5P	99.68	66.63	1294

Literature-anchored findings (GeneRIF, showing 40)

• no correlation between the number of tandem repeats and scoliosis severity (PMID:11898616)
• Cleavage of the carboxyl tail from the G3 domain of aggrecan but not versican and identification of the amino acids involved in the degradation (PMID:11932252)
• cleaved by ADAMTS1 and diffrenteially inhibited by metalloproteinase inhibitors (PMID:12054629)
• Peptide p135H, corresponding to the peptide sequence in the G3 domain of human cartilage proteoglycan aggrecan, is immunogenic/arthritogenic in BALB/c mice (PMID:14558103)
• The amount of aggrecan may be related to motor aspects of intermittent exotropia (PMID:14627072)
• alternative splicing in the aggrecan G3 domain may be a mechanism for modulating interactions and extracellular matrix assembly (PMID:14722076)
• the interaction between aggrecan and hyaluronan in cartilage is stabilized by Link protein (PMID:14724283)
• peptide fingerprinting showed that cartilage link protein and AG1 interact in the absence or presence of hyaluronan (PMID:15590670)
• Data demonstrate a significant reduction of collagens I, II and aggrecan mRNA after the initiation of culture compared with mRNA levels in fresh tissue. (PMID:16001263)
• A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. (PMID:16080123)
• variable number of tandem repeat polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis patients, in 217 HTLV-I-infected healthy carriers, and in 85 normal controls (PMID:16402214)
• relationship between aggrecan structure and function; role of polymorphism in intervertebral disc and articular cartilage degeneratin [review] (PMID:16425147)
• establishing directly the relative residence time of these molecules in human intervertebral disc matrix (PMID:16537531)
• the cleavage of aggregable aggrecan occurred in concrete peptide bonds within the CS-1 and CS-2 attachment domains (PMID:16574327)
• This study demonstrates that elevated aggrecan expression and its secretion are aberrant features of Hutchinson-Gilford Progeria Syndrome. (PMID:16650460)
• Despite the negative association reported here, further investigation of the gene and its potential association to familial idiopathic scoliosis is required. (PMID:16741449)
• Results show an aggrecan product with the COOH terminal neoepitope VPGVA is synthesized by intracellular processing in chondrocytes; M-calpain is the major candidate of the proteinase to generate this product during intracellular aggrecan processing. (PMID:17261541)
• Human cells cultured over 5 days increased expression of aggrecan and collagen II in both nucleus and annulus cells under increasing osmolarity. (PMID:17568421)
• COMP/TSP5 may function to support matrix interactions with aggrecan in cartilage extracellular matrix (PMID:17588949)
• The findings provide additional support for the role of the aggrecan gene VNTR polymorphism in intervertebral disc degeneration. (PMID:17632389)
• mRNAs for type II collagen and aggrecan were expressed by MSCs treated with either TGFbeta1 or OP-1; however, substantial matrix production was not induced. (PMID:18040638)
• we conclude from the region-specific patterns that the aggrecan-based extracellular matrix is adapted to the fast processing of sensorimotor activities (PMID:18055126)
• The number of aggrecan-based perineural nets in the parietal cortex of transgenic mice is not significantly reduced when compared to the wild-type. There is a loss of hyaluronan and aggrecan components in the amyloid plaque core and coronal zone. (PMID:18829133)
• there was an association between the aggrecan gene variable number of tandem repeats polymorphism and rheumatoid arthritis (PMID:19004047)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• There is a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height. (PMID:19110214)
• in the human cerebral cortex, discrete, layer-specific PNNs are assembled through the participation of selected aggrecan isoforms that characterize defined subsets of cortical neurons (PMID:19220578)
• Aggrecan was deposited in the myxoid and chondroid stroma of salivary pleomorphic adenomas. (PMID:19294492)
• Results indicate that CCN2/CTGF binds to aggrecan through its N-terminal IGFBP and VWC modules, and this binding may be related to the CCN2/CTGF-enhanced production and secretion of aggrecan by chondrocytes. (PMID:19298220)
• Application of both mechanical loads resulted in significant alterations of gene expression of PTN (+67%, P = 0.004 in anulus cells; +29%, P = 0.03 in nucleus cells) and aggrecan (+42%, P = 0.03 in anulus cells, -25%, P = 0.03 in nucleus cells). (PMID:19333097)
• Levels of aggrecan ARGS fragments in human synovial fluid are increased in arthritis, osteoarthritis and following knee injury. (PMID:19545413)
• A novel HtrA1-susceptible cleavage site within the interglobular domain (IGD) of aggrecan was identified. (PMID:19657146)
• The aggrecan was prominently immunolocalised in the cartilaginous vertebral body rudiments and to a lesser extent within the foetal intervertebral disc. (PMID:19669783)
• Hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia-inducible factor 1alpha-dependent redifferentiation of chondrocytes. (PMID:19790048)
• A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the osteochondritis dissecans. (PMID:20137779)
• An underlying additive and multiplicative interaction is observed between the aggrecan gene VNTR polymorphism and smoking in symptomatic disc degeneration of Chinese Han in northern China. (PMID:20367118)
• This study revealed that the polymorphisms of the VDR and aggrecan genes are associated with disc degeneration and herniation. (PMID:20367178)
• Carrying shorter AGC1 alleles with less than 24 repeats could predispose a subject to lumbar disk degeneration disease in northern Iran. (PMID:20496110)
• Data show an association between the distribution of aggrecan gene VNTR polymorphism and the expression of aggrecan in symptomatic LDH. (PMID:20505571)
• Data indicate that calpains are involved in the C-terminal truncation of aggrecan and might have a minor role in arthritic diseases. (PMID:20618160)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	acana	ENSDARG00000035891
danio_rerio	acanb	ENSDARG00000045799
mus_musculus	Acan	ENSMUSG00000030607
rattus_norvegicus	Acan	ENSRNOG00000028992

Paralogs (7): VCAN (ENSG00000038427), NCAN (ENSG00000130287), BCAN (ENSG00000132692), HAPLN2 (ENSG00000132702), HAPLN3 (ENSG00000140511), HAPLN1 (ENSG00000145681), HAPLN4 (ENSG00000187664)

Protein

Protein identifiers

Aggrecan core protein — P16112 (reviewed: P16112)

Alternative names: Cartilage-specific proteoglycan core protein, Chondroitin sulfate proteoglycan core protein 1

All UniProt accessions (4): A0A5K1VW97, P16112, H0YK70, Q6PID9

UniProt curated annotations — full annotation on UniProt →

Function. This proteoglycan is a major component of extracellular matrix of cartilagenous tissues. A major function of this protein is to resist compression in cartilage. It binds avidly to hyaluronic acid via an N-terminal globular region.

Subunit / interactions. Forms a complex (via covalent bonds) with MATN1; the interaction increases with age of the organism via an increase in occupancy of MATN1 binding sites. Interacts with FBLN1. Interacts with COMP.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Detected in fibroblasts (at protein level). Restricted to cartilage.

Post-translational modifications. Contains mostly chondroitin sulfate, but also keratan sulfate chains, N-linked and O-linked oligosaccharides. The release of aggrecan fragments from articular cartilage into the synovial fluid at all stages of human osteoarthritis is the result of cleavage by aggrecanase.

Disease relevance. Spondyloepiphyseal dysplasia type Kimberley (SEDK) [MIM:608361] Spondyloepiphyseal dysplasias are a heterogeneous group of congenital chondrodysplasias that specifically affect epiphyses and vertebrae. The autosomal dominant SEDK is associated with premature degenerative arthropathy. The disease is caused by variants affecting the gene represented in this entry. Spondyloepimetaphyseal dysplasia, aggrecan type (SEMDAG) [MIM:612813] A bone disease characterized by severe short stature, macrocephaly, severe midface hypoplasia, short neck, barrel chest and brachydactyly. The radiological findings comprise long bones with generalized irregular epiphyses with widened metaphyses, especially at the knees, platyspondyly, and multiple cervical-vertebral clefts. The disease is caused by variants affecting the gene represented in this entry. Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) [MIM:165800] An autosomal dominant disease characterized by short stature, advanced bone maturation, early-onset osteoarthritis, and mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disk disease and osteochondritis dissecans. Osteochondritis dissecans is defined as a separation of cartilage and subchondral bone from the surrounding tissue. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Two globular domains, G1 and G2, comprise the N-terminus of the proteoglycan, while another globular region, G3, makes up the C-terminus. G1 contains Link domains and thus consists of three disulfide-bonded loop structures designated as the A, B, B’ motifs. G2 is similar to G1. The keratan sulfate (KS) and the chondroitin sulfate (CS) attachment domains lie between G2 and G3.

Similarity. Belongs to the aggrecan/versican proteoglycan family.

Isoforms (4)

UniProt ID	Names	Canonical?
P16112-1	1	yes
P16112-2	2
P16112-3	3
P16112-4	4

RefSeq proteins (5): NP_001126, NP_001356197, NP_001398025, NP_001398026, NP_037359 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000538	Link_dom	Domain
IPR000742	EGF	Domain
IPR001304	C-type_lectin-like	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR018378	C-type_lectin_CS	Conserved_site
IPR033987	CSPG_CTLD	Domain
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050691	Hyaluronan_bind_Proteoglycan	Family

Pfam: PF00059, PF00084, PF00193, PF07686

UniProt features (165 total): repeat 47, region of interest 21, glycosylation site 18, sequence variant 17, disulfide bond 16, compositionally biased region 11, sequence conflict 10, binding site 10, domain 8, splice variant 3, chain 2, signal peptide 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4MD4	X-RAY DIFFRACTION	1.95
9DFF	X-RAY DIFFRACTION	2.59
7RDV	X-RAY DIFFRACTION	2.9
9DFT	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16112-F1	53.32	0.17

Functional residue map

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

Catalytic / active sites (1): 392–393 (cleavage; by aggrecanase)

Ligand- & substrate-binding residues (10): 2381; 2385; 2405; 2407; 2408; 2414; 2414; 2415; 2428; 2429

Disulfide bonds (16): 51–133, 175–246, 199–220, 273–348, 297–318, 500–571, 524–545, 598–673, 622–643, 2283–2293, 2288–2302, 2304–2313, 2348–2440, 2416–2432, 2447–2490, 2476–2503

Glycosylation sites (18): 126, 239, 333, 371, 376, 387, 434, 602, 658, 738, 1530, 1567, 1581, 1587, 1591, 1601, 1703, 2013

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-2022854	Keratan sulfate biosynthesis
R-HSA-2022857	Keratan sulfate degradation
R-HSA-3000178	ECM proteoglycans
R-HSA-3656225	Defective CHST6 causes MCDC1
R-HSA-3656243	Defective ST3GAL3 causes MCT12 and EIEE15
R-HSA-3656244	Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)

MSigDB gene sets: 250 (showing top): CREL_01, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, AREB6_01, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GGGTGGRR_PAX4_03, LIEN_BREAST_CARCINOMA_METAPLASTIC, TTGCWCAAY_CEBPB_02, CEBPB_01, NFKB_C, MARTINEZ_RB1_TARGETS_DN, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT

GO Biological Process (4): skeletal system development (GO:0001501), proteolysis (GO:0006508), cell adhesion (GO:0007155), central nervous system development (GO:0007417)

GO Molecular Function (7): extracellular matrix structural constituent (GO:0005201), hyaluronic acid binding (GO:0005540), carbohydrate binding (GO:0030246), metal ion binding (GO:0046872), calcium ion binding (GO:0005509), protein binding (GO:0005515), extracellular matrix structural constituent conferring compression resistance (GO:0030021)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), extracellular matrix (GO:0031012), lysosomal lumen (GO:0043202), synapse (GO:0045202), perineuronal net (GO:0072534)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Diseases associated with glycosaminoglycan metabolism	3
Extracellular matrix organization	2
Keratan sulfate/keratin metabolism	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
binding	2
protein metabolic process	1
cellular process	1
nervous system development	1
structural molecule activity	1
extracellular matrix	1
carboxylic acid binding	1
cation binding	1
metal ion binding	1
extracellular matrix structural constituent	1
cellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
external encapsulating structure	1
lysosome	1
vacuolar lumen	1
cell junction	1
perisynaptic extracellular matrix	1

Protein interactions and networks

STRING

2194 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACAN	FN1	P02751	994
ACAN	PTPRZ1	P23471	990
ACAN	BCAN	Q96GW7	983
ACAN	VCAN	P13611	980
ACAN	ADAMTS4	O75173	970
ACAN	DCN	P07585	962
ACAN	ADAMTS3	O15072	961
ACAN	ADAMTS5	Q9UNA0	955
ACAN	COMP	P49747	954
ACAN	FBLN1	P23142	951
ACAN	NCAN	O14594	949
ACAN	HAPLN1	P10915	925
ACAN	BGN	P13247	921
ACAN	MMP13	P45452	909
ACAN	ELN	P15502	909

IntAct

6 interactions, top by confidence:

A	B	Type	Score
APP	ACAN	psi-mi:“MI:0915”(physical association)	0.560
PCOLCE	ACAN	psi-mi:“MI:0407”(direct interaction)	0.440
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WGB1, C7DZK3, O35206, O60279, O88207, O89103, P07897, P13608, P13942, P16112, P20908, P20909, P25940, P39059, P39060, P39061, P55068, P83371, Q07092, Q14767, Q17RW2, Q28019, Q28062, Q28343, Q28670, Q29011, Q30D77, Q32S24, Q3MI99, Q4ZJM7, Q5QNQ9, Q60467, Q61245, Q61282, Q64739, Q6UXH8

Diamond homologs: A5PMY6, A6QP79, D3ZWT9, O14594, P02706, P02707, P05451, P06734, P07306, P07307, P07897, P07898, P08290, P08661, P10716, P10758, P11226, P13608, P13611, P16112, P19999, P20693, P22897, P24721, P34927, P41317, P43137, P48304, P49300, P49301, P55066, P55067, P60883, P70194, P81282, P82596, P86854, Q28343, Q28670, Q29011

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
SIRT1	“up-regulates quantity by expression”	ACAN	“transcriptional regulation”
ACAN	up-regulates	ECM_synthesis
ADAMTS4	“down-regulates quantity by destabilization”	ACAN	cleavage
ADAMTS5	“down-regulates quantity by destabilization”	ACAN	cleavage
MMP3	“down-regulates quantity by destabilization”	ACAN	cleavage
ACAN	“up-regulates activity”	“Av/b3 integrin”	binding
ACAN	“up-regulates activity”	“A5/b1 integrin”	binding
MMP19	“down-regulates quantity by destabilization”	ACAN	cleavage
MMP20	“down-regulates quantity by destabilization”	ACAN	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

1704 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	136
Likely pathogenic	68
Uncertain significance	905
Likely benign	369
Benign	140

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069109	NM_001369268.1(ACAN):c.1097dup (p.Gly366_Glu367insTer)	Pathogenic
1189835	NM_001369268.1(ACAN):c.492C>A (p.Tyr164Ter)	Pathogenic
1199200	NM_001369268.1(ACAN):c.1552_1556del (p.Glu518fs)	Pathogenic
1321150	NM_001369268.1(ACAN):c.6049G>T (p.Glu2017Ter)	Pathogenic
1328336	NM_001369268.1(ACAN):c.1608C>A (p.Tyr536Ter)	Pathogenic
1332835	NM_001369268.1(ACAN):c.1605-2A>C	Pathogenic
1353164	NM_001369268.1(ACAN):c.902G>A (p.Trp301Ter)	Pathogenic
1362760	NM_001369268.1(ACAN):c.7096C>T (p.Gln2366Ter)	Pathogenic
1425149	NM_001369268.1(ACAN):c.7410C>A (p.Cys2470Ter)	Pathogenic
1426035	NM_001369268.1(ACAN):c.867del (p.Trp290fs)	Pathogenic
14304	NM_001369268.1(ACAN):c.3758dup (p.Gly1254fs)	Pathogenic
14306	NM_001369268.1(ACAN):c.7363G>A (p.Val2455Met)	Pathogenic
1444952	NM_001369268.1(ACAN):c.1022C>G (p.Ser341Ter)	Pathogenic
1451967	NM_001369268.1(ACAN):c.987C>G (p.Tyr329Ter)	Pathogenic
1460224	NC_000015.9:g.(?89379438)(89417712_?)del	Pathogenic
1520307	NM_001369268.1(ACAN):c.630-13G>A	Pathogenic
1526221	NM_001369268.1(ACAN):c.301C>T (p.Gln101Ter)	Pathogenic
1685497	NM_001369268.1(ACAN):c.4474del (p.Ser1492fs)	Pathogenic
1929461	NM_001369268.1(ACAN):c.1411C>T (p.Gln471Ter)	Pathogenic
1976848	NM_001369268.1(ACAN):c.6918del (p.Gly2307fs)	Pathogenic
1992362	NM_001369268.1(ACAN):c.2002dup (p.Arg668fs)	Pathogenic
2020061	NM_001369268.1(ACAN):c.1929C>A (p.Cys643Ter)	Pathogenic
2027279	NM_001369268.1(ACAN):c.633C>A (p.Tyr211Ter)	Pathogenic
2028361	NM_001369268.1(ACAN):c.7086G>A (p.Trp2362Ter)	Pathogenic
2050442	NM_001369268.1(ACAN):c.1349del (p.Leu450fs)	Pathogenic
2052120	NM_001369268.1(ACAN):c.392del (p.Tyr131fs)	Pathogenic
2068482	NM_001369268.1(ACAN):c.103del (p.Gln35fs)	Pathogenic
2077548	NM_001369268.1(ACAN):c.1603A>T (p.Arg535Ter)	Pathogenic
2096900	NM_001369268.1(ACAN):c.954C>A (p.Cys318Ter)	Pathogenic
2110819	NM_001369268.1(ACAN):c.589del (p.His197fs)	Pathogenic

SpliceAI

3118 predictions. Top by Δscore:

Variant	Effect	Δscore
15:88836272:TTCAG:T	donor_loss	1.0000
15:88836273:TCAG:T	donor_loss	1.0000
15:88836274:CAG:C	donor_loss	1.0000
15:88836275:AGG:A	donor_loss	1.0000
15:88836276:GG:G	donor_loss	1.0000
15:88836277:G:T	donor_loss	1.0000
15:88836278:T:G	donor_loss	1.0000
15:88838649:C:G	acceptor_gain	1.0000
15:88838658:CACA:C	acceptor_loss	1.0000
15:88838659:A:AG	acceptor_gain	1.0000
15:88838659:ACAGA:A	acceptor_loss	1.0000
15:88838660:C:G	acceptor_gain	1.0000
15:88838660:CA:C	acceptor_loss	1.0000
15:88838661:A:AG	acceptor_gain	1.0000
15:88838662:G:A	acceptor_loss	1.0000
15:88838662:G:GA	acceptor_gain	1.0000
15:88838662:GA:G	acceptor_gain	1.0000
15:88838662:GAC:G	acceptor_gain	1.0000
15:88838662:GACC:G	acceptor_gain	1.0000
15:88838662:GACCA:G	acceptor_gain	1.0000
15:88839031:G:GT	donor_gain	1.0000
15:88839044:AAGG:A	donor_loss	1.0000
15:88839045:AGGT:A	donor_loss	1.0000
15:88839047:GTGAG:G	donor_loss	1.0000
15:88839048:T:A	donor_loss	1.0000
15:88840184:CAGG:C	donor_loss	1.0000
15:88840185:AGGTG:A	donor_loss	1.0000
15:88841727:G:A	acceptor_gain	1.0000
15:88843647:AGGTG:A	donor_loss	1.0000
15:88843648:GGTGG:G	donor_loss	1.0000

AlphaMissense

16389 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:88838815:T:A	W75R	1.000
15:88838815:T:C	W75R	1.000
15:88840080:T:C	C175R	1.000
15:88840082:C:G	C175W	1.000
15:88840120:T:C	L188P	1.000
15:88840152:T:A	C199S	1.000
15:88840152:T:C	C199R	1.000
15:88840153:G:C	C199S	1.000
15:88840164:T:A	W203R	1.000
15:88840164:T:C	W203R	1.000
15:88840166:G:C	W203C	1.000
15:88840166:G:T	W203C	1.000
15:88841846:T:C	C246R	1.000
15:88841848:C:G	C246W	1.000
15:88843500:G:C	W301C	1.000
15:88843500:G:T	W301C	1.000
15:88847351:T:C	L513P	1.000
15:88872023:T:A	W2376R	1.000
15:88872023:T:C	W2376R	1.000
15:88872025:G:C	W2376C	1.000
15:88872025:G:T	W2376C	1.000
15:88872971:T:A	W2427R	1.000
15:88872971:T:C	W2427R	1.000
15:88872973:G:C	W2427C	1.000
15:88872973:G:T	W2427C	1.000
15:88838684:T:A	V31D	0.999
15:88838743:T:C	C51R	0.999
15:88838817:G:C	W75C	0.999
15:88838817:G:T	W75C	0.999
15:88838987:G:C	R132P	0.999

dbSNP variants (sampled 300 via entrez): RS1000003858 (15:88854083 G>A), RS1000004316 (15:88873459 G>A), RS1000035452 (15:88873722 C>T), RS1000077515 (15:88801726 C>G,T), RS1000091938 (15:88814938 C>G,T), RS1000096180 (15:88844262 G>A), RS1000231579 (15:88807199 T>G), RS1000232452 (15:88825942 G>A), RS1000357076 (15:88812120 C>T), RS1000367190 (15:88812259 T>C), RS1000377657 (15:88867403 C>G), RS1000410216 (15:88820765 T>C,G), RS1000417091 (15:88837538 C>T), RS1000456840 (15:88851121 C>T), RS1000460106 (15:88866844 C>G)

Disease associations

OMIM: gene MIM:155760 | disease phenotypes: MIM:612813, MIM:608361, MIM:165800, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans	Definitive	Autosomal dominant
spondyloepiphyseal dysplasia, Kimberley type	Definitive	Autosomal dominant
spondyloepimetaphyseal dysplasia, aggrecan type	Definitive	Autosomal recessive
ACAN-related short stature spectrum	Definitive	Autosomal dominant
osteochondritis dissecans	Definitive	Autosomal dominant
short stature-advanced bone age-early-onset osteoarthritis syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ACAN-related short stature spectrum	Definitive	AD

Mondo (9): spondyloepimetaphyseal dysplasia, aggrecan type (MONDO:0013014), osteochondritis dissecans (MONDO:0017178), spondyloepiphyseal dysplasia, Kimberley type (MONDO:0012019), short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MONDO:0100462), Meniere disease (MONDO:0007972), skeletal dysplasia (MONDO:0018230), short stature-advanced bone age-early-onset osteoarthritis syndrome (MONDO:0018566), ACAN-related short stature spectrum (MONDO:1060149), spondyloepiphyseal dysplasia (MONDO:0016761)

Orphanet (9): Spondyloepimetaphyseal dysplasia, aggrecan type (Orphanet:171866), Familial osteochondritis dissecans (Orphanet:251262), Osteochondritis dissecans (Orphanet:2764), Spondyloepiphyseal dysplasia, Kimberley type (Orphanet:93283), Primary bone dysplasia (Orphanet:364526), Short stature-advanced bone age-early-onset osteoarthritis syndrome (Orphanet:435804), Spondyloepiphyseal dysplasia and spondyloepimetaphyseal dysplasia (Orphanet:253), NON RARE IN EUROPE: Menière disease (Orphanet:45360), OBSOLETE: Spondyloepimetaphyseal dysplasia (Orphanet:252)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000272	Malar flattening
HP:0000303	Mandibular prognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000470	Short neck
HP:0000926	Platyspondyly
HP:0001156	Brachydactyly
HP:0001382	Joint hypermobility
HP:0001552	Barrel-shaped chest
HP:0001597	Abnormal nail morphology
HP:0001609	Hoarse voice
HP:0002007	Frontal bossing
HP:0002515	Waddling gait
HP:0002651	Spondyloepimetaphyseal dysplasia
HP:0002655	Spondyloepiphyseal dysplasia
HP:0002750	Delayed skeletal maturation
HP:0002758	Osteoarthritis
HP:0002795	Abnormal respiratory system physiology
HP:0002857	Genu valgum
HP:0002938	Lumbar hyperlordosis
HP:0002970	Genu varum
HP:0002983	Micromelia
HP:0003016	Metaphyseal widening
HP:0003027	Mesomelia
HP:0003088	Premature osteoarthritis
HP:0003370	Flat capital femoral epiphysis
HP:0003508	Proportionate short stature
HP:0004322	Short stature

GWAS associations

96 associations (top):

Study	Trait	p-value
GCST000174_12	Height	8.000000e-08
GCST000817_31	Height	1.000000e-14
GCST000817_61	Height	4.000000e-27
GCST001263_5	Height	2.000000e-09
GCST001956_52	Height	1.000000e-15
GCST002573_1	Height	4.000000e-07
GCST002646_9	Infant length	6.000000e-09
GCST002647_114	Height	3.000000e-44
GCST002702_73	Height	9.000000e-11
GCST003763_1	Age-related hearing impairment	3.000000e-13
GCST003763_3	Age-related hearing impairment	4.000000e-11
GCST004063_152	Waist circumference adjusted for body mass index	3.000000e-10
GCST004063_157	Waist circumference adjusted for body mass index	8.000000e-06
GCST004067_62	Hip circumference adjusted for BMI	4.000000e-08
GCST004212_1	Height	1.000000e-11
GCST004500_22	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	1.000000e-07
GCST004500_93	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	9.000000e-07
GCST004501_36	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	8.000000e-08
GCST004501_37	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-06
GCST004504_19	Waist circumference adjusted for BMI in non-smokers	5.000000e-06
GCST004504_20	Waist circumference adjusted for BMI in non-smokers	7.000000e-06
GCST004562_152	Waist circumference adjusted for body mass index	2.000000e-08
GCST004562_248	Waist circumference adjusted for body mass index	1.000000e-07
GCST004562_48	Waist circumference adjusted for body mass index	2.000000e-09
GCST004563_134	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	4.000000e-09
GCST004563_210	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	6.000000e-07
GCST004563_29	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	3.000000e-08
GCST004564_107	Waist circumference adjusted for BMI in active individuals	1.000000e-06
GCST004564_108	Waist circumference adjusted for BMI in active individuals	1.000000e-09
GCST004564_109	Waist circumference adjusted for BMI in active individuals	2.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0006785	infant body height
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004229	Dupuytren Contracture
EFO:0004341	body fat distribution
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008575	Meniere Disease	C09.218.568.217.500
D010008	Osteochondritis Dissecans	C05.116.791.668
C567558	Spondyloepimetaphyseal Dysplasia, Aggrecan Type (supp.)
C564252	Spondyloepiphyseal Dysplasia, Kimberley Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Dexamethasone	affects cotreatment, decreases reaction, increases expression, decreases expression	6
Glucosamine	decreases reaction, decreases cleavage, decreases secretion, affects expression, affects reaction (+2 more)	5
T-2 Toxin	decreases expression	3
bisphenol A	affects cotreatment, decreases expression, decreases methylation	2
bisphenol S	decreases methylation, affects cotreatment, decreases expression	2
Resveratrol	increases expression, affects cotreatment, decreases expression, decreases reaction	2
bisphenol F	affects cotreatment, decreases expression	1
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	increases cleavage, increases expression	1
deoxynivalenol	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
HT-2 toxin	decreases expression, increases cleavage	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
diacerein	decreases expression, decreases reaction, increases expression	1
tamibarotene	affects expression	1
glucosamine 3-O-sulfate	decreases expression	1
alpinetin	decreases expression, decreases reaction	1
abrine	increases expression	1
irigenin	decreases reaction, decreases expression	1
dulaglutide	increases degradation, decreases reaction	1
Dasatinib	increases expression	1
Alginic Acid	increases expression	1
Amino Acids, Peptides, and Proteins	increases degradation, decreases reaction	1
Ascorbic Acid	decreases reaction, increases expression, affects cotreatment	1
Azacitidine	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Berberine	decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Melatonin	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01283737	PHASE4	WITHDRAWN	Use of Demineralised Bone Matrix (DBX) in Osteochondritis Dissecans (OCD)
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT01498029	PHASE3	UNKNOWN	Knee Articular Cartilage Repair: Cartilage Autograft Implantation System Versus Conventional Microfracture
NCT02993510	PHASE3	COMPLETED	A Randomized Controlled Trial Comparing Chondro-Gide® to Microfracture Alone for Treatment of Knee Cartilage Defects.
NCT03588975	PHASE3	RECRUITING	A Study of MACI in Patients Aged 10 to 17 Years With Symptomatic Chondral or Osteochondral Defects of the Knee
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease
NCT01694823	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy Study of Cells Sheet-Autologous Chondrocyte Implantation to Treat Articular Cartilage Defects
NCT01159899	EARLY_PHASE1	UNKNOWN	Transplantation of Bone Marrow Stem Cells Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee
NCT00881023	Not specified	TERMINATED	Cartilage Autograft Implantation System (CAIS) for the Repair of Knee Cartilage Through Cartilage Regeneration
NCT01329445	Not specified	UNKNOWN	DeNovo NT Longitudinal Data Collection (LDC) Knee Study
NCT01347892	Not specified	UNKNOWN	DeNovo NT Ankle LDC Study
NCT01409447	Not specified	UNKNOWN	Repair of Articular Osteochondral Defect
NCT01455987	Not specified	UNKNOWN	Osteochondritis Dissecans of the Knee
NCT01458782	Not specified	ACTIVE_NOT_RECRUITING	ACI-C Versus AMIC. A Randomized Trial Comparing Two Methods for Repair of Cartilage Defects in the Knee
NCT01471236	Not specified	COMPLETED	Evaluation of the Agili-C Biphasic Implant in the Knee Joint
NCT02397278	Not specified	COMPLETED	Intra Articular Injections With Platelet Rich Plasma in Patients With Juvenile Osteochondritis Dissecans of the Knee
NCT02664337	Not specified	ENROLLING_BY_INVITATION	Conjoint Analysis of Patient Preferences in Joint Interventions
NCT02771496	Not specified	RECRUITING	Osteochondritis Dissecans of Knee Prospective Cohort
NCT03452098	Not specified	COMPLETED	Post-Operative Rehabilitation of Knee Osteochondral Defect: A Case Series
NCT03656185	Not specified	UNKNOWN	Elbow Arthroscopy Data Analysis
NCT04297449	Not specified	COMPLETED	Prospective 2-year Data Collection of the First 10 Patients After Ankle Spacer Implantation
NCT04364334	Not specified	RECRUITING	Knee Registry (Knieregister)
NCT06462040	Not specified	RECRUITING	Evaluation of Clinical and Radiological Outcomes in Patients Undergoing Fixation of Osteochondral Fragments With Reasorbable Screws in the Knee Joint
NCT07332182	Not specified	NOT_YET_RECRUITING	MaioRegen Prime Study for the Treatment of Deep Osteochondral Lesion of the Knee
NCT07439107	Not specified	ACTIVE_NOT_RECRUITING	Treatment Outcomes for Osteochondritis Dissecans of the Knee: A Cohort Study
NCT04218123	PHASE2/PHASE3	COMPLETED	Assessing the Efficacy of a Serotonin and Norepinephrine Reuptake Inhibitor for Improving Meniere’s Disease Outcomes
NCT04766853	PHASE1/PHASE2	COMPLETED	Verification of the Efficacy/safety of the Intratympanic Drug Delivery for Hearing Loss
NCT04794842	EARLY_PHASE1	UNKNOWN	Comparing Topical Tetracaine Drops to Topical Focal Phenol for Local Anesthesia During Intratympanic Steroid Injection
NCT00599560	Not specified	COMPLETED	Vasopressin and V2 Receptor in Meniere’s Disease
NCT02371798	Not specified	WITHDRAWN	Unilateral Meniere Disease: Can Double Dose Gadolinium and Delayed Imaging Make the Diagnosis?
NCT03520322	Not specified	TERMINATED	A Study of a Mastoid Device in Subjects With Ménière’s Disease
NCT03795675	Not specified	ACTIVE_NOT_RECRUITING	CI Following VS Removal or Labyrinthectomy
NCT04370366	Not specified	RECRUITING	Imaging of Endolymphatic Hydrops at 7T MRI