MATN4

Summary

MATN4 (matrilin 4, HGNC:6910) is a protein-coding gene on chromosome 20q13.12, encoding Matrilin-4 (O95460). Major component of the extracellular matrix of cartilage.

This gene encodes a member of von Willebrand factor A domain-containing protein family. The proteins of this family are thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This family member is thought to be play a role in reorganizing and regenerating the corneal matrix in granular and lattice type I dystrophies. It may also be involved in wound healing in the dentin-pulp complex. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8785 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 120 total — 1 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001393530

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6910
Approved symbol	MATN4
Name	matrilin 4
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000124159
Ensembl biotype	protein_coding
OMIM	603897
Entrez	8785

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 nonsense_mediated_decay

ENST00000353917, ENST00000360607, ENST00000372754, ENST00000372756, ENST00000537548, ENST00000686119, ENST00000874026, ENST00000922695, ENST00000922696, ENST00000922697

RefSeq mRNA: 5 — MANE Select: NM_001393530 NM_001393530, NM_001393531, NM_003833, NM_030590, NM_030592

CCDS: CCDS13348, CCDS46607

Canonical transcript exons

ENST00000372756 — 10 exons

Exon	Start	End
ENSE00000844930	45297918	45298070
ENSE00000844932	45298170	45298583
ENSE00000844938	45301321	45301443
ENSE00000844941	45304228	45304797
ENSE00000906908	45300887	45301009
ENSE00000906910	45301102	45301224
ENSE00001224295	45305510	45305616
ENSE00001306994	45293908	45294015
ENSE00003707325	45293450	45293825
ENSE00003925840	45308175	45308299

Expression profiles

Bgee: expression breadth broad, 96 present calls, max score 87.55.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1693 / max 74.6373, expressed in 26 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187418	0.1693	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	87.55	gold quality
body of pancreas	UBERON:0001150	87.18	gold quality
buccal mucosa cell	CL:0002336	85.75	silver quality
skin of hip	UBERON:0001554	72.54	gold quality
upper arm skin	UBERON:0004263	72.31	silver quality
tibia	UBERON:0000979	70.00	gold quality
secondary oocyte	CL:0000655	69.36	gold quality
endometrium epithelium	UBERON:0004811	69.00	gold quality
pancreatic ductal cell	CL:0002079	68.52	silver quality
parotid gland	UBERON:0001831	68.31	gold quality
upper leg skin	UBERON:0004262	68.03	gold quality
pancreas	UBERON:0001264	67.49	gold quality
skin of leg	UBERON:0001511	63.51	gold quality
zone of skin	UBERON:0000014	63.16	gold quality
oocyte	CL:0000023	63.12	gold quality
frontal pole	UBERON:0002795	63.04	gold quality
middle frontal gyrus	UBERON:0002702	62.94	gold quality
vena cava	UBERON:0004087	62.79	silver quality
paraflocculus	UBERON:0005351	62.60	gold quality
skin of abdomen	UBERON:0001416	61.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	60.76	gold quality
decidua	UBERON:0002450	59.66	gold quality
cerebellar vermis	UBERON:0004720	57.39	gold quality
nasal cavity mucosa	UBERON:0001826	57.12	gold quality
oviduct epithelium	UBERON:0004804	55.54	gold quality
mucosa of sigmoid colon	UBERON:0004993	54.73	gold quality
tendon of biceps brachii	UBERON:0008188	54.52	gold quality
vastus lateralis	UBERON:0001379	54.33	gold quality
quadriceps femoris	UBERON:0001377	54.25	gold quality
epithelium of nasopharynx	UBERON:0001951	54.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.14

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 2)

• Matrilin 4 (MATN4) was the only ECM biogenesis and organization related gene detected in odontoblasts but not in pulp by microarray and RT-PCR. MATN4 protein expression only in odontoblasts was confirmed by Western blot. (PMID:18005044)
• MATN4 as a target gene of HIF-1alpha promotes the proliferation and metastasis of osteosarcoma. (PMID:38889378)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	matn4	ENSDARG00000015947
mus_musculus	Matn4	ENSMUSG00000016995
rattus_norvegicus	Matn4	ENSRNOG00000014021

Paralogs (12): COCH (ENSG00000100473), COL12A1 (ENSG00000111799), MATN3 (ENSG00000132031), MATN2 (ENSG00000132561), MATN1 (ENSG00000162510), COL6A3 (ENSG00000163359), VWA2 (ENSG00000165816), COL6A5 (ENSG00000172752), VWA1 (ENSG00000179403), COL14A1 (ENSG00000187955), VIT (ENSG00000205221), COL6A6 (ENSG00000206384)

Protein

Protein identifiers

Matrilin-4 — O95460 (reviewed: O95460)

All UniProt accessions (3): A0A8I5KYX9, A6NNA4, O95460

UniProt curated annotations — full annotation on UniProt →

Function. Major component of the extracellular matrix of cartilage.

Subunit / interactions. Interacts with COMP.

Subcellular location. Secreted.

Tissue specificity. Embryonic kidney, lung and placenta.

Isoforms (4)

UniProt ID	Names	Canonical?
O95460-1	1	yes
O95460-2	2
O95460-3	3
O95460-4	4

RefSeq proteins (5): NP_001380459, NP_001380460, NP_003824, NP_085080, NP_085095 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002035	VWF_A	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR019466	Matrilin_CC_trimer	Domain
IPR026823	cEGF	Domain
IPR036337	Matrilin_CC_sf	Homologous_superfamily
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR050525	ECM_Assembly_Org	Family

Pfam: PF00092, PF10393, PF12662, PF14670

UniProt features (31 total): disulfide bond 12, domain 6, glycosylation site 3, splice variant 3, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95460-F1	82.10	0.37

Functional residue map

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

Disulfide bonds (12): 219–230, 226–239, 241–254, 260–271, 267–280, 282–295, 301–312, 308–321, 323–336, 342–353, 349–362, 364–377

Glycosylation sites (3): 251, 305, 69

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3000178	ECM proteoglycans
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 82 (showing top): SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM6, ONGUSAHA_TP53_TARGETS, MORF_WNT1, DBP_Q6, BURTON_ADIPOGENESIS_8, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, MORF_IL9, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, LEIN_ASTROCYTE_MARKERS, ZHANG_GATA6_TARGETS_DN, MORF_FRK, NIKOLSKY_BREAST_CANCER_20Q12_Q13_AMPLICON, SWEET_LUNG_CANCER_KRAS_UP, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3

GO Biological Process (1): extracellular matrix organization (GO:0030198)

GO Molecular Function (2): calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), extracellular matrix (GO:0031012), matrilin complex (GO:0120216)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular structure organization	1
external encapsulating structure organization	1
metal ion binding	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1
non-collagenous component of interstitial matrix	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

1133 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MATN4	COL9A3	Q14050	642
MATN4	COL9A1	P20849	569
MATN4	EPYC	Q99645	560
MATN4	WFDC12	Q8WWY7	476
MATN4	CNMD	O75829	460
MATN4	COL9A2	Q14055	440
MATN4	SEMG2	Q02383	433
MATN4	PI3	P19957	425
MATN4	SEMG1	P04279	418
MATN4	SLPI	P03973	417
MATN4	GAS2	O43903	403
MATN4	COL2A1	P02458	379
MATN4	ACAN	P16112	370
MATN4	SPEF1	Q9Y4P9	364
MATN4	LINGO2	Q7L985	360

IntAct

5 interactions, top by confidence:

A	B	Type	Score
MYC		psi-mi:“MI:0914”(association)	0.350
REPIN1	POTEB	psi-mi:“MI:0914”(association)	0.350
GMEB1	MATN4	psi-mi:“MI:0914”(association)	0.350
MATN4	HSPA5	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): VIPAS39 (Affinity Capture-MS), VPS33B (Affinity Capture-MS), CILP2 (Affinity Capture-MS), MATN1 (Affinity Capture-MS), MATN4 (Affinity Capture-MS), NACC1 (Affinity Capture-MS), BCS1L (Affinity Capture-MS), ARG2 (Affinity Capture-MS), ZMYM2 (Affinity Capture-MS), MATN4 (Two-hybrid), MATN4 (Two-hybrid), MATN4 (Two-hybrid), SDCBP (Two-hybrid), WDYHV1 (Two-hybrid), ACSF3 (Two-hybrid)

ESM2 similar proteins: A2AX52, A2VE29, A6H584, A8TX70, E1BMV3, E7FF10, O00339, O08746, O15232, O35701, O42401, O89029, O95460, P00743, P00751, P04186, P05099, P06681, P12111, P13944, P15989, P21941, P24063, P51942, P61625, P79263, P81187, Q03710, Q05910, Q0IIH7, Q14393, Q14624, Q29052, Q3SYW2, Q3T052, Q4R7B7, Q5GFL6, Q5RER0, Q60677, Q63772

Diamond homologs: A2AX52, A6QLN9, E1BMV3, E7FF10, O00339, O08746, O15232, O35701, O42163, O42401, O43405, O75578, O89029, O95460, P05099, P12111, P13944, P15989, P17301, P18614, P21941, P24063, P32018, P51942, P53710, P56199, P84552, Q02388, Q21540, Q3V3R4, Q5EA64, Q5GFL6, Q60847, Q62507, Q63870, Q642A6, Q6DCQ6, Q6PCB0, Q6UXI7, Q70UZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	95
Likely benign	6
Benign	13

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
183295	NM_001393530.1(MATN4):c.515G>C (p.Gly172Ala)	Likely pathogenic

SpliceAI

2172 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45297913:CTCA:C	donor_loss	1.0000
20:45297914:TCACC:T	donor_loss	1.0000
20:45297915:CA:C	donor_loss	1.0000
20:45297916:A:AC	donor_gain	1.0000
20:45297916:A:AT	donor_loss	1.0000
20:45297917:C:CC	donor_gain	1.0000
20:45298067:ATGCC:A	acceptor_loss	1.0000
20:45298068:TGCCT:T	acceptor_loss	1.0000
20:45298071:C:CC	acceptor_gain	1.0000
20:45298071:C:CG	acceptor_loss	1.0000
20:45298072:T:G	acceptor_loss	1.0000
20:45298166:CCACC:C	donor_loss	1.0000
20:45298167:CACCT:C	donor_loss	1.0000
20:45298168:ACC:A	donor_loss	1.0000
20:45298169:CC:C	donor_loss	1.0000
20:45298172:T:A	donor_gain	1.0000
20:45298175:T:TA	donor_gain	1.0000
20:45298208:T:TA	donor_gain	1.0000
20:45300883:TCACG:T	donor_loss	1.0000
20:45300884:CA:C	donor_loss	1.0000
20:45300885:A:AC	donor_gain	1.0000
20:45300886:C:CG	donor_gain	1.0000
20:45300886:CG:C	donor_gain	1.0000
20:45300886:CGG:C	donor_gain	1.0000
20:45300886:CGGTT:C	donor_gain	1.0000
20:45300900:G:A	donor_gain	1.0000
20:45301005:CCGGA:C	acceptor_gain	1.0000
20:45301006:CGGA:C	acceptor_gain	1.0000
20:45301006:CGGAC:C	acceptor_gain	1.0000
20:45301007:GGA:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000376271 (20:45296587 C>T), RS1000751678 (20:45307612 T>A), RS1001038825 (20:45294281 T>A), RS1001325171 (20:45301550 C>G,T), RS1001714596 (20:45300769 A>G), RS1001767109 (20:45300272 A>G,T), RS1002211614 (20:45294794 G>A), RS1003235689 (20:45303721 A>C), RS1003336029 (20:45298360 G>T), RS1003455534 (20:45303451 G>A,C), RS1003663994 (20:45302880 C>G,T), RS1003721428 (20:45296680 A>G), RS1003778605 (20:45303302 T>C), RS1004248766 (20:45295613 C>A), RS1004406294 (20:45302059 G>A)

Disease associations

OMIM: gene MIM:603897 | disease phenotypes: MIM:236100, MIM:125853

GenCC curated gene-disease

Mondo (5): microcephaly (MONDO:0001149), exophthalmos (MONDO:0004770), diabetes insipidus (MONDO:0004782), holoprosencephaly (MONDO:0016296), type 2 diabetes mellitus (MONDO:0005148)

Orphanet (1): Holoprosencephaly (Orphanet:2162)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly
HP:0000520	Proptosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_695	Blood protein levels	2.000000e-23
GCST010725_40	Malaria	1.000000e-06

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003919	Diabetes Insipidus	C12.050.351.968.419.135; C12.200.777.419.135; C12.950.419.135; C19.700.159
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D005094	Exophthalmos	C11.675.349
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
beauvericin	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
ferrous chloride	increases expression	1
pentanal	increases expression	1
enniatins	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estradiol	affects cotreatment, decreases expression	1
Lead	increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus