MATN3

Summary

MATN3 (matrilin 3, HGNC:6909) is a protein-coding gene on chromosome 2p24.1, encoding Matrilin-3 (O15232). Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.

This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia.

Source: NCBI Gene 4148 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple epiphyseal dysplasia type 5 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 379 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 67
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002381

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6909
Approved symbol	MATN3
Name	matrilin 3
Location	2p24.1
Locus type	gene with protein product
Status	Approved
Aliases	EDM5, HOA
Ensembl gene	ENSG00000132031
Ensembl biotype	protein_coding
OMIM	602109
Entrez	4148

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000407540, ENST00000421259, ENST00000478482, ENST00000856777

RefSeq mRNA: 1 — MANE Select: NM_002381 NM_002381

CCDS: CCDS46226

Canonical transcript exons

ENST00000407540 — 8 exons

Exon	Start	End
ENSE00000901173	19997134	19997259
ENSE00000901174	20000441	20000566
ENSE00000901175	20001955	20002080
ENSE00000901176	20003161	20003286
ENSE00000901177	20005744	20006310
ENSE00000901178	20012409	20012668
ENSE00001549249	19994299	19994409
ENSE00001562550	19992052	19993166

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 99.12.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7041 / max 57.0951, expressed in 700 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27072	1.6145	684
27073	0.0895	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.12	gold quality
cartilage tissue	UBERON:0002418	89.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.17	gold quality
right lung	UBERON:0002167	81.76	gold quality
tibial nerve	UBERON:0001323	80.87	gold quality
upper lobe of left lung	UBERON:0008952	77.71	gold quality
upper lobe of lung	UBERON:0008948	77.34	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	77.27	gold quality
spinal cord	UBERON:0002240	73.42	gold quality
lower lobe of lung	UBERON:0008949	72.78	gold quality
stromal cell of endometrium	CL:0002255	71.98	gold quality
amygdala	UBERON:0001876	71.42	gold quality
lung	UBERON:0002048	70.88	gold quality
left uterine tube	UBERON:0001303	70.40	gold quality
gall bladder	UBERON:0002110	69.59	gold quality
endocervix	UBERON:0000458	68.65	gold quality
thoracic aorta	UBERON:0001515	68.47	gold quality
ascending aorta	UBERON:0001496	68.43	gold quality
descending thoracic aorta	UBERON:0002345	68.12	gold quality
endothelial cell	CL:0000115	68.04	silver quality
substantia nigra	UBERON:0002038	67.64	gold quality
cingulate cortex	UBERON:0003027	67.63	gold quality
omental fat pad	UBERON:0010414	67.51	gold quality
peritoneum	UBERON:0002358	67.43	gold quality
anterior cingulate cortex	UBERON:0009835	67.33	gold quality
hypothalamus	UBERON:0001898	67.16	gold quality
metanephros cortex	UBERON:0010533	67.13	gold quality
aorta	UBERON:0000947	66.86	gold quality
left coronary artery	UBERON:0001626	66.64	gold quality
prefrontal cortex	UBERON:0000451	66.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1

miRNA regulators (miRDB)

76 targeting MATN3, 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-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-944	99.82	70.85	3042

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutation in MATN3 had significant association for patients with osteoarthritis. (PMID:12736871)
• Four novel missense mutations and one recurrent missense mutation were identified in MATN3 in seven families with multiple epiphyseal dysplasia. (PMID:14729835)
• MATN3 mutations is associated with multiple epiphyseal dysplasia (PMID:14994237)
• Contrary to the previous assumption that the MATN3 mutation in multiple epiphyseal dysplasia is confined to the beta-sheet regions, one novel mutation is located outside the beta-sheet region, within an alpha-helix region (PMID:15459972)
• COMP, type IX collagen and MATN3 play important roles in matrix assembly (PMID:15694129)
• mutations in matrilin-3 causing chondrodysplasias (R116W and C299S) interfere with intracellular protein trafficking and formation of filamentous extracellular structures (PMID:16199550)
• Multiple epiphyseal dysplasia caused by MATN3 mutations is the result of an intracellular retention of the mutant protein. (PMID:16287128)
• Patients carrying the T(303)M mutation in the gene for matrilin-3 express a form of HOA that is radiologically indistinguishable from idiopathic HOA in individual patients but they have more severe thumb-base involvement, particularly in the STT joint. (PMID:16641049)
• We have demonstrated intergenic splicing between two sets of family genes, the matrilin-3 (MATN3) and lysosomal-associated protein transmembrane 4alpha (LAPTM4A). (PMID:16769693)
• recombinant ADAMTS-4 effectively cleaved intact matrilin-3 at the predicted motif at Glu435/Ala436 generating two species of 45 and 5 kDa (PMID:17311924)
• a matn3 mutation causes decreased chondrocyte proliferation and dysregulated apoptosis leading to epiphyseal dysplasia (PMID:17517694)
• the matrilin-3 A-domain appears to bind exclusively to the COL3 domain of type IX collagen and this binding is abolished in the presence of a disease causing mutation in type IX collagen (PMID:17881354)
• The characterization of two additional alpha-helical mutations (p.Ala173Asp and p.Lys231Asn) is described. Both p.Phe105Ser and pAla173Asp prevent the secretion of A-domain in vitro. (PMID:18205203)
• increased expression of MATN3 in osteoarthritis might contribute to the degeneration of articular cartilage. (PMID:18759284)
• potential of matrilin-3 to modulate gene expression profile of primary chondrocytes; tested matrilin3-dependent induction of pro-inflammatory cytokines, inducible nitric oxide synthetase & cyclooxygenase-2, MMP1, -3 & -13, & matrilin-3 itself (PMID:19840795)
• a matrilin-3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils (PMID:20077500)
• MATN3 mutations were identified in 13 multiple epiphyseal dysplasia patients and comprised predominantly of missense mutations. (PMID:21922596)
• Radiographic findings in patients with COMP and MATN3 mutations showed marked abnormalities in hip and knee joints. (PMID:21965141)
• Haplotype-4 of MATN3 is associated with vertebral fracture risk independent of bone mineral density in Chinese postmenopausal women. (PMID:22270056)
• MATN3 plays a regulatory role in cartilage homeostasis due to its capacity to induce IL-1Ra, upregulate gene expression of major cartilage matrix components, and downregulate the expression of OA-associated matrix-degrading proteinases in chondrocytes. (PMID:22967398)
• Polymorphism in the MATN3 gene might play a role in osteoarthritis in the Chinese Han population. (PMID:22973175)
• The VWA1 domain of matrilin-3 is primarily responsible for the induction of IL-6 release from primary human chondrocytes. (PMID:23523902)
• This report is the first to show the involvement of MATN3 in C-type natriuretic peptide/natriuretic peptide receptor-B signaling pathway during the process of transforming growth factor-beta induced chondrogenic differentiation of mesenchymal stem cells. (PMID:24934313)
• MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity (PMID:25331953)
• The results of the study indicate a potential role for the MATN3 rs28598872 polymorphism in the pathogenesis of Temporomandibular Joint Internal Derangement. (PMID:27533128)
• Study confirmed that MATN3 protein was highly expressed in GAC patients, and MATN3 overexpression could be used as an independent predictor of poor prognosis in GAC patients. (PMID:29343680)
• miR-448 contributed to the progression of osteoarthritis by directly targeting matrilin-3. (PMID:29483929)
• Our data highlights the importance of detection and careful characterization of intragenic duplication CNVs, presenting them as a novel and very rare genetic mechanism in IFT81-related Jeune syndrome and MATN3-related MED. (PMID:30080953)
• MATN3 Mutation Causing Spondyloepimetaphyseal Dysplasia. (PMID:31724101)
• Analysis of Polymorphisms in the MATN3 and DOT1L Genes and CTX-II Urinary Levels in Patients with Knee Osteoarthritis in a Northeast Mexican-Mestizo Population. (PMID:31999490)
• A novel p.A191D matrilin-3 variant in a Vietnamese family with multiple epiphyseal dysplasia: a case report. (PMID:32264862)
• A novel homozygous missense variant in MATN3 causes spondylo-epimetaphyseal dysplasia Matrilin 3 type in a consanguineous family. (PMID:32470407)
• Matrilin-3 alleviates extracellular matrix degradation of nucleus pulposus cells via induction of IL-1 receptor antagonist. (PMID:32495856)
• Differentiation of Hypertrophic Chondrocytes from Human iPSCs for the In Vitro Modeling of Chondrodysplasias. (PMID:33636111)
• Exosomal MATN3 of Urine-Derived Stem Cells Ameliorates Intervertebral Disc Degeneration by Antisenescence Effects and Promotes NPC Proliferation and ECM Synthesis by Activating TGF-beta. (PMID:34136064)
• Identification of MATN3 as a Novel Prognostic Biomarker for Gastric Cancer through Comprehensive TCGA and GEO Data Mining. (PMID:34900024)
• Curcumin Reduces Pathological Endoplasmic Reticulum Stress through Increasing Proteolysis of Mutant Matrilin-3. (PMID:36675026)
• The phase separation of extracellular matrix protein matrilin-3 from cancer-associated fibroblasts contributes to gastric cancer invasion. (PMID:38193601)
• [Relationship Between the Expression of Human Matricellular Protein 3 and the Pathological Features, Drug Resistance, and Prognosis of Gastric Cancer Based on Immunohistochemical Method]. (PMID:39170027)
• Amino acid metabolism-related genes as potential biomarkers and the role of MATN3 in stomach adenocarcinoma: A bioinformatics, mendelian randomization and experimental validation study. (PMID:39353384)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	matn3a	ENSDARG00000069245
danio_rerio	matn3b	ENSDARG00000069265
mus_musculus	Matn3	ENSMUSG00000020583
rattus_norvegicus	Matn3	ENSRNOG00000056141

Paralogs (12): COCH (ENSG00000100473), COL12A1 (ENSG00000111799), MATN4 (ENSG00000124159), MATN2 (ENSG00000132561), MATN1 (ENSG00000162510), COL6A3 (ENSG00000163359), VWA2 (ENSG00000165816), COL6A5 (ENSG00000172752), VWA1 (ENSG00000179403), COL14A1 (ENSG00000187955), VIT (ENSG00000205221), COL6A6 (ENSG00000206384)

Protein

Protein identifiers

Matrilin-3 — O15232 (reviewed: O15232)

All UniProt accessions (1): O15232

UniProt curated annotations — full annotation on UniProt →

Function. Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.

Subunit / interactions. Can form homooligomers (monomers, dimers, trimers and tetramers) and heterooligomers with matrilin-1. Interacts with COMP. Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4.

Subcellular location. Secreted.

Tissue specificity. Expressed only in cartilaginous tissues, such as vertebrae, ribs and shoulders.

Disease relevance. Multiple epiphyseal dysplasia 5 (EDM5) [MIM:607078] A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. Multiple epiphyseal dysplasia type 5 is relatively mild and clinically variable. It is primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. The disease is caused by variants affecting the gene represented in this entry. Spondyloepimetaphyseal dysplasia, Borochowitz-Cormier-Daire type (SEMDBCD) [MIM:608728] An autosomal recessive bone disease characterized by disproportionate early-onset dwarfism, bowing of the lower limbs, lumbar lordosis and normal hands. Skeletal abnormalities include short, wide and stocky long bones with severe epiphyseal and metaphyseal changes, hypoplastic iliac bones and flat, ovoid vertebral bodies. The disease is caused by variants affecting the gene represented in this entry. Osteoarthritis 2 (OS2) [MIM:140600] A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. In the hand, osteoarthritis can develop in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints. Patients with osteoarthritis may have one, a few, or all of these sites affected. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O15232-1	1	yes
O15232-2	2

RefSeq proteins (1): NP_002372* (*=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
IPR049883	NOTCH1_EGF-like	Domain
IPR050525	ECM_Assembly_Org	Family

Pfam: PF00092, PF07645, PF10393, PF12662, PF14670

UniProt features (46 total): sequence variant 20, disulfide bond 12, domain 5, modified residue 3, signal peptide 1, chain 1, splice variant 1, region of interest 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15232-F1	79.79	0.45

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 (3): 198, 441, 442

Disulfide bonds (12): 268–279, 275–289, 291–304, 310–321, 317–331, 333–346, 352–363, 359–373, 375–388, 394–405, 401–415, 417–430

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-3000178	ECM proteoglycans
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-1474244	Extracellular matrix organization
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 243 (showing top): TAATAAT_MIR126, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOZGIT_ESR1_TARGETS_DN, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GOBP_CONNECTIVE_TISSUE_DEVELOPMENT, RGAGGAARY_PU1_Q6, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_A, DELACROIX_RARG_BOUND_MEF, REACTOME_ECM_PROTEOGLYCANS

GO Biological Process (3): skeletal system development (GO:0001501), extracellular matrix organization (GO:0030198), cartilage development (GO:0051216)

GO Molecular Function (3): extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), matrilin complex (GO:0120216)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	1
extracellular structure organization	1
external encapsulating structure organization	1
skeletal system development	1
animal organ development	1
connective tissue development	1
structural molecule activity	1
extracellular matrix	1
metal ion binding	1
binding	1
cellular anatomical structure	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
non-collagenous component of interstitial matrix	1
extracellular protein-containing complex	1

Protein interactions and networks

STRING

1873 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MATN3	FRZB	Q92765	953
MATN3	ASPN	Q9BXN1	934
MATN3	CTDSP2	O14595	925
MATN3	COL9A3	Q14050	919
MATN3	COL9A2	Q14055	914
MATN3	SLC26A2	P50443	906
MATN3	COL9A1	P20849	878
MATN3	COMP	P49747	797
MATN3	GDF5	P43026	757
MATN3	DTNB	O60941	600
MATN3	HAPLN1	P10915	590
MATN3	GINS2	Q9Y248	588
MATN3	HDAC3	O15379	580
MATN3	HDAC8	Q9BY41	574
MATN3	KIF3C	O14782	569

IntAct

27 interactions, top by confidence:

A	B	Type	Score
MATN3	TCF4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	MATN3	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	MATN3	psi-mi:“MI:0915”(physical association)	0.560
TCF4	MATN3	psi-mi:“MI:0915”(physical association)	0.560
MATN3	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
MATN3	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
MATN3	PDIA4	psi-mi:“MI:0914”(association)	0.560
MATN3	PDIA4	psi-mi:“MI:0915”(physical association)	0.560
MATN3	INCA1	psi-mi:“MI:0915”(physical association)	0.560
MATN3	TF	psi-mi:“MI:0914”(association)	0.530
COL2A1	MATN3	psi-mi:“MI:0407”(direct interaction)	0.440
MATN3	COMP	psi-mi:“MI:0407”(direct interaction)	0.440
MATN3	Creld2	psi-mi:“MI:0915”(physical association)	0.400
MATN3	P4HB	psi-mi:“MI:0914”(association)	0.350
MATN3	EDIL3	psi-mi:“MI:0914”(association)	0.350
MATN3	TCF4	psi-mi:“MI:0915”(physical association)	0.000
MATN3	INCA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): TCF4 (Two-hybrid), KRTAP10-8 (Two-hybrid), NOTCH2NL (Two-hybrid), TF (Affinity Capture-MS), PBLD (Affinity Capture-MS), TF (Affinity Capture-MS), PBLD (Affinity Capture-MS), GDA (Affinity Capture-MS), INCA1 (Two-hybrid), TCF4 (Two-hybrid), MATN3 (Proximity Label-MS), GDA (Affinity Capture-MS), PBLD (Affinity Capture-MS), EDIL3 (Affinity Capture-MS), TF (Affinity Capture-MS)

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, A6H584, A6NMZ7, A8TX70, E7FF10, O00339, O08746, O15232, O35701, O42401, P05555, P11215, P12111, P13944, P15989, P17301, P18614, P32018, P34576, P53710, P61622, Q02388, Q13349, Q21281, Q21540, Q28902, Q3V0T4, Q3V3R4, Q62469, Q63870, Q641F3, Q6UXI7, Q8C6K9, Q8NFW1, Q8R2Z5, Q8VHI5, Q90615, Q91145, Q923P0, Q95LI2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	225
Likely benign	79
Benign	31

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1299496	NC_000002.12:g.19998776_20009244dup	Pathogenic
7540	NM_002381.5(MATN3):c.581T>A (p.Val194Asp)	Pathogenic
7543	NM_002381.5(MATN3):c.656C>A (p.Ala219Asp)	Pathogenic
7544	NM_002381.5(MATN3):c.910T>A (p.Cys304Ser)	Pathogenic
7546	NM_002381.5(MATN3):c.382G>C (p.Ala128Pro)	Pathogenic
1675209	NM_002381.5(MATN3):c.400G>A (p.Glu134Lys)	Likely pathogenic
1683458	NM_002381.5(MATN3):c.368C>T (p.Ala123Val)	Likely pathogenic
3641292	NM_002381.5(MATN3):c.154C>G (p.Pro52Ala)	Likely pathogenic
4280636	NM_002381.5(MATN3):c.359C>G (p.Thr120Arg)	Likely pathogenic
560181	NM_002381.5(MATN3):c.224-2153_1168+903dup	Likely pathogenic
931804	NM_002381.5(MATN3):c.59TGC[3] (p.Leu23del)	Likely pathogenic

SpliceAI

1082 predictions. Top by Δscore:

Variant	Effect	Δscore
2:19997269:CGTGG:C	acceptor_gain	1.0000
2:19997277:A:T	acceptor_gain	1.0000
2:20003155:CCTCA:C	donor_loss	1.0000
2:20003156:CTCAC:C	donor_loss	1.0000
2:20003157:TCA:T	donor_loss	1.0000
2:20003158:CA:C	donor_loss	1.0000
2:20003282:CAGCG:C	acceptor_gain	1.0000
2:20003283:AGCG:A	acceptor_gain	1.0000
2:20003284:GCG:G	acceptor_gain	1.0000
2:20003285:CG:C	acceptor_gain	1.0000
2:20003285:CGC:C	acceptor_gain	1.0000
2:20003285:CGCTG:C	acceptor_loss	1.0000
2:20003286:GC:G	acceptor_loss	1.0000
2:20003287:C:CC	acceptor_gain	1.0000
2:20003287:CTGTG:C	acceptor_loss	1.0000
2:20005740:TTACC:T	donor_loss	1.0000
2:20005741:TACCA:T	donor_loss	1.0000
2:20005742:A:AC	donor_gain	1.0000
2:20005742:ACCAC:A	donor_loss	1.0000
2:20005743:C:CC	donor_gain	1.0000
2:20005743:CCA:C	donor_gain	1.0000
2:20006308:CAC:C	acceptor_gain	1.0000
2:20006309:ACC:A	acceptor_loss	1.0000
2:20006311:C:CC	acceptor_gain	1.0000
2:19994410:C:CC	acceptor_gain	0.9900
2:19997270:G:C	acceptor_gain	0.9900
2:19997273:G:C	acceptor_gain	0.9900
2:19997273:G:GC	acceptor_gain	0.9900
2:19997276:C:CT	acceptor_gain	0.9900
2:19997297:A:C	acceptor_gain	0.9900

AlphaMissense

3156 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:20006262:G:A	S91F	0.999
2:20006264:A:C	S90R	0.999
2:20006264:A:T	S90R	0.999
2:20006266:T:G	S90R	0.999
2:20006268:T:A	D89V	0.999
2:20005947:T:A	D196V	0.998
2:20005953:A:T	V194D	0.998
2:20006167:C:G	A123P	0.998
2:20006238:A:C	F99C	0.998
2:20006262:G:T	S91Y	0.998
2:20006269:C:G	D89H	0.998
2:20006277:A:G	F86S	0.998
2:20006283:A:G	L84P	0.998
2:20005872:C:T	G221D	0.997
2:20006040:G:T	A165D	0.997
2:20006237:G:C	F99L	0.997
2:20006237:G:T	F99L	0.997
2:20006239:A:G	F99L	0.997
2:20006267:A:C	D89E	0.997
2:20006267:A:T	D89E	0.997
2:20006268:T:G	D89A	0.997
2:20005761:A:C	F258C	0.996
2:20005845:A:G	L230P	0.996
2:20005845:A:T	L230H	0.996
2:20005878:G:T	A219D	0.996
2:20005946:A:C	D196E	0.996
2:20005946:A:T	D196E	0.996
2:20005948:C:G	D196H	0.996
2:20006152:C:G	A128P	0.996
2:20006217:A:T	V106D	0.996

dbSNP variants (sampled 300 via entrez): RS1000304336 (2:20013907 G>A), RS1000345586 (2:20003489 C>T), RS1000383854 (2:19995150 T>C), RS1000682592 (2:20001901 G>A,T), RS1000818119 (2:19995375 C>G,T), RS1000947713 (2:20014413 G>A,C), RS1000984916 (2:20001574 G>A), RS1001120858 (2:19993419 C>T), RS1001262015 (2:20007933 A>G,T), RS1001553303 (2:20007451 C>G), RS1001595653 (2:19996214 A>C), RS1001691072 (2:19996325 A>G), RS1001819857 (2:20010201 G>A), RS1002144826 (2:20002423 G>C), RS1002271239 (2:20008223 A>T)

Disease associations

OMIM: gene MIM:602109 | disease phenotypes: MIM:132400, MIM:607078, MIM:140600, MIM:608728, MIM:177170

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple epiphyseal dysplasia type 5	Definitive	Autosomal dominant
spondyloepimetaphyseal dysplasia, matrilin-3 type	Strong	Autosomal recessive

Mondo (6): multiple epiphyseal dysplasia (MONDO:0016648), multiple epiphyseal dysplasia type 5 (MONDO:0011765), connective tissue disorder (MONDO:0003900), osteoarthritis susceptibility 2 (MONDO:0007704), spondyloepimetaphyseal dysplasia, matrilin-3 type (MONDO:0012108), pseudoachondroplasia (MONDO:0008322)

Orphanet (4): Multiple epiphyseal dysplasia (Orphanet:251), Multiple epiphyseal dysplasia type 5 (Orphanet:93311), Spondyloepimetaphyseal dysplasia, matrilin-3 type (Orphanet:156728), Pseudoachondroplasia (Orphanet:750)

HPO phenotypes

67 total (30 of 67 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000767	Pectus excavatum
HP:0000922	Posterior rib cupping
HP:0000926	Platyspondyly
HP:0001216	Delayed ossification of carpal bones
HP:0001288	Gait disturbance
HP:0001377	Limited elbow extension
HP:0001384	Abnormal hip joint morphology
HP:0001385	Hip dysplasia
HP:0001387	Joint stiffness
HP:0002515	Waddling gait
HP:0002651	Spondyloepimetaphyseal dysplasia
HP:0002654	Multiple epiphyseal dysplasia
HP:0002656	Epiphyseal dysplasia
HP:0002758	Osteoarthritis
HP:0002812	Coxa vara
HP:0002829	Arthralgia
HP:0002857	Genu valgum
HP:0002938	Lumbar hyperlordosis
HP:0002970	Genu varum
HP:0002979	Bowing of the legs
HP:0002980	Femoral bowing
HP:0002983	Micromelia
HP:0003016	Metaphyseal widening
HP:0003025	Metaphyseal irregularity
HP:0003026	Short long bone
HP:0003037	Enlarged joints
HP:0003088	Premature osteoarthritis
HP:0003090	Hypoplasia of the capital femoral epiphysis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90020027_1592	Waist-hip index	4.000000e-08
GCST90020029_640	Waist circumference adjusted for body mass index	8.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
C535505	Epiphyseal dysplasia, multiple, 5 (supp.)
C535819	Pseudoachondroplasia (supp.)
C563869	Spondyloepimetaphyseal Dysplasia, Matrilin-3 Related (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Nickel	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases methylation, affects cotreatment	1
dicrotophos	decreases expression	1
bisphenol A	affects expression	1
formononetin	decreases expression	1
terbufos	increases methylation	1
3,4-dichloroaniline	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
perfluorohexanesulfonic acid	increases expression	1
abrine	decreases expression	1
quinocetone	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT03866200	PHASE2	TERMINATED	Resveratrol Trial for Relief of Pain in Pseudoachondroplasia
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00341679	Not specified	COMPLETED	Studies of the Natural History and Pathogenesis of Autoimmune/Connective Tissue Diseases
NCT00470327	Not specified	RECRUITING	A Study of the Natural Progression of Interstitial Lung Disease (ILD)