| 2005 |
MED-causing MATN3 mutations in the A-domain cause misfolding of that domain (shown by unfolded conformation of mutant A-domains expressed individually) and prevent secretion of matrilin-3 from mammalian cells; mutant protein is retained intracellularly. Co-immunoprecipitation demonstrated that mutant A-domains associate specifically with ERp72, an ER chaperone involved in disulfide bond formation. Electron microscopy of patient cartilage confirmed intracellular retention in dilated rough ER cisternae. |
Mammalian cell expression of wild-type and mutant matrilin-3, co-immunoprecipitation with ERp72, electron microscopy and immunohistochemistry of patient cartilage |
Human mutation |
High |
16287128
|
| 2007 |
In a knock-in mouse model carrying a Matn3 MED mutation, mutant matrilin-3 is retained within the rough ER of chondrocytes and triggers an unfolded protein response (UPR), leading to decreased chondrocyte proliferation and spatially dysregulated apoptosis in the cartilage growth plate, which disrupts linear bone growth and causes short-limbed dwarfism. |
Mouse knock-in model, histochemistry, immunohistochemistry, electron microscopy, assessment of chondrocyte proliferation and apoptosis in growth plate |
Human molecular genetics |
High |
17517694
|
| 2008 |
Two alpha-helical A-domain mutations (p.Phe105Ser and p.Ala173Asp) prevent secretion of matrilin-3 A-domain in vitro, similar to beta-sheet mutations. However, a third alpha-helical mutation (p.Lys231Asn) does not prevent A-domain secretion, does not disrupt A-domain structure, and does not inhibit binding to type II or type IX collagen, leaving its disease mechanism unresolved. |
In vitro A-domain expression and secretion assay, structural assessment, collagen binding assay |
Human mutation |
Medium |
18205203
|
| 2012 |
Secretion of mutant matrilin-3 (V194D) is not dependent on hetero-oligomerization with matrilin-1; ablation of matrilin-1 expression in Matn3 V194D mice does not alter the proportion of mutant matrilin-3 in the ECM, does not increase intracellular retention, and does not worsen disease severity. Retained mutant matrilin-3 forms non-native disulfide-bonded aggregates through the misfolded A-domain and causes co-retention of matrilin-1. |
Genetic cross of Matn3 V194D knock-in with Matn1-null mice; histochemistry, biochemistry (disulfide-bonded aggregate analysis), phenotypic assessment |
Arthritis and rheumatism |
High |
22083516
|
| 1998 |
Human MATN3 encodes a 486 amino acid extracellular matrix protein with the domain architecture: signal peptide, von Willebrand factor A (vWFA) domain, four EGF repeats, and an alpha-helical coiled-coil region. The mRNA is expressed in all cartilage types and by primary (but not dedifferentiated) chondrocytes, suggesting matrilin-3 as a marker of chondrocyte differentiation state. |
cDNA cloning from cartilage library, sequence analysis, Northern blot / expression in primary vs. dedifferentiated chondrocytes |
Genomics |
Medium |
9799608
|
| 2000 |
The mouse Matn3 gene comprises 8 exons spanning 23.4 kb; the last intron uses non-canonical AT-AC ends and is spliced by the U12-type spliceosome, a feature conserved in all matrilin genes. Unlike other matrilins, Matn3 lacks a second vWFA domain; the intron that could encode it contains 75% repetitive sequences indicating evolutionary loss. |
Genomic cloning, exon mapping, RNase protection assay for transcription start sites, SSCP mapping |
Mammalian genome |
Medium |
10656920
|
| 2004 |
All characterized MED-causing MATN3 mutations cluster within exon 2 encoding the vWFA (A) domain, specifically in and around the 2nd beta-sheet region (amino acids 120-127). One novel mutation (p.F105S) extends the affected region to an alpha-helix of the A-domain, outside the beta-sheet. |
PCR and direct sequencing of all 8 MATN3 exons in MED patients |
Human mutation |
Medium |
15459972
|
| 2018 |
An intragenic de novo tandem duplication of exons 2–5 in MATN3 (formed via Alu-Alu mediated recombination) causes multiple epiphyseal dysplasia, establishing intragenic CNV as a novel mutational mechanism for MATN3-related disease. |
Targeted CNV screening, breakpoint characterization (Alu-Alu fusion identification) |
Human mutation |
Low |
30080953
|
| 2021 |
Exosomal MATN3 protein from urine-derived stem cells promotes nucleus pulposus cell (NPC) proliferation and ECM synthesis, and alleviates intervertebral disc degeneration in vivo. The mechanism involves MATN3 activating TGF-β signaling, elevating phosphorylation of SMAD and AKT. MATN3 was identified as the required cargo mediating these USC-exosome effects by knockdown experiments. |
Western blot, CCK-8 proliferation assay, immunofluorescence, in vivo IDD mouse model (CT, MRI, histology), MATN3 knockdown in exosomes |
Oxidative medicine and cellular longevity |
Medium |
34136064
|
| 2023 |
SMSC-derived exosomal MATN3 suppresses activation of the PI3K/AKT/mTOR signaling pathway through IL-17A, protecting chondrocytes from ECM degradation and autophagy defects in an OA model. |
In vitro OA model (IL-1β), SMSC-Exo administration, overexpression and knockdown of MATN3, Western blot for PI3K/AKT/mTOR pathway components, in vivo mouse OA model (DMM surgery) |
Journal of orthopaedic translation |
Medium |
37635810
|
| 2024 |
In gastric cancer, MATN3 interacts directly with ASPN (Co-IP/PPI analysis) and promotes cell proliferation, migration, and invasion; MATN3 knockdown inhibits these behaviors and induces apoptosis. Co-overexpression of MATN3 and ASPN in vivo enhances tumor growth and metastasis, indicating synergistic oncogenic activity through EMT pathway activation. |
Protein-protein interaction analysis, co-expression analysis, functional assays (proliferation, migration, invasion, apoptosis), in vivo xenograft mouse model |
Human molecular genetics |
Medium |
39301785
|
| 2026 |
GC-derived exosomal MATN3 interacts with EGFR (confirmed by Co-IP and co-localization by immunofluorescence), enhances EGFR protein stability, activates ELK1 transcription factor, which promotes ATG12-mediated autophagy activation, leading to M2 macrophage polarization and immunosuppressive tumor microenvironment. Mechanistic confirmation by ChIP, dual-luciferase reporter, ubiquitination assay. |
Co-IP, immunofluorescence co-localization, Western blot, RT-qPCR, ChIP assay, dual-luciferase reporter assay, ubiquitination assay, xenograft mouse model, co-culture of GC-Exo with macrophages |
Immunology |
Medium |
42163458
|
| 2026 |
In a human pluripotent stem cell (hPSC) model of MED with MATN3 mutations, mutant matrilin-3 causes upregulation of the cholesterol biosynthesis pathway and abnormal ECM matrix assembly, accompanied by distended ER, accumulation of lipid droplets, and increased cholesterol content in chondrocyte pellets. Some UPR marker gene expression was slightly increased. |
hPSC differentiation to chondrocytes, CRISPR-Cas9 gene editing and patient PBMC reprogramming, RNAseq, transmission electron microscopy, immunohistochemistry |
Osteoarthritis and cartilage |
Medium |
41651153
|