MMP2
protein-codingmatrix metallopeptidase 2, the group of M10 matrix metallopeptidases
Gene summary
This gene is a member of the matrix metalloproteinase (MMP) gene family, that are zinc-dependent enzymes capable of cleaving components of the extracellular matrix and molecules involved in signal transduction. The protein encoded by this gene is a gelatinase A, type IV collagenase, that contains three fibronectin type II repeats in its catalytic site that allow binding of denatured type IV and V collagen and elastin. Unlike most MMP family members, activation of this protein can occur on the cell membrane. This enzyme can be activated extracellularly by proteases, or, intracellulary by its S-glutathiolation with no requirement for proteolytical removal of the pro-domain. This protein is thought to be involved in multiple pathways including roles in the nervous system, endometrial menstrual breakdown, regulation of vascularization, and metastasis. Mutations in this gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis (NAO) syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]
- CLG4
- CLG4A
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~117.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009809
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0018298
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009809
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009809
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MMP2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004530.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 95 | 4 | 101 | ||
| missense | 2 | 4 | 160 | 6 | 4 | 176 |
| nonsense | 10 | 2 | 1 | 13 | ||
| start loss | 1 | 1 | ||||
| frameshift | 7 | 2 | 2 | 11 | ||
| splice donor/acceptor (+/-2bp) | 4 | 9 | 13 | |||
| Total | 19 | 12 | 175 | 101 | 8 | 315 |
Highest pathogenic variant AF is 0.000055757868
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004521.1 | 13 | MANE Select | |
| Ensembl | ENSP00000219070.4 | 13 | MANE Select | |
| RefSeq | NP_001121363.1 | 13 | Standard | |
| RefSeq | NP_001289437.1 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mmp2 | Danio rerio | Structure: interrenal angiogenic sprout Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Relaxin signaling pathway - Homo sapiens (human)
- AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
- Bladder cancer - Homo sapiens (human)
- GnRH signaling pathway - Homo sapiens (human)
- Estrogen signaling pathway - Homo sapiens (human)
Biological Process
- angiogenesis
- response to hypoxia
- blood vessel maturation
- intramembranous ossification
- proteolysis
Molecular Function
- metalloendopeptidase activity
- serine-type endopeptidase activity
- protein binding
- metallopeptidase activity
- zinc ion binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- mitochondrion
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219070
- Coding exons
- 13
- Length
- 116992
- Individuals with no LoFs
- 125726
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 125748
- p
- 0.0000875
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.710 | 351 | 390 | 0.899 | 0.0000246 | 4364 |
| Missense (PolyPhen) | 146 | 173.35 | 0.84223 | 1850 | ||
| Synonymous | -1.27 | 178 | 158 | 1.13 | 0.0000106 | 1242 |
| Loss of Function | 4.30 | 6 | 32.4 | 0.185 | 0.00000168 | 364 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Involved in the formation of the fibrovascular tissues in association with MMP14.; FUNCTION: Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro- inflammatory NF-kappaB, NFAT and IRF transcriptional pathways.;
- Disease
- DISEASE: Multicentric osteolysis, nodulosis, and arthropathy (MONA) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. {ECO:0000269|PubMed:11431697, ECO:0000269|PubMed:15691365, ECO:0000269|PubMed:16542393}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.962
Intolerance Scores
- LoFtool
- 0.202
- RVIS EVS
- -0.06
- RVIS percentile EVS
- 48.84
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.725
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |