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FLASH GENE
Symbol COL18A1 contributors: SGE - updated : 18-01-2018
HGNC name collagen, type XVIII, alpha 1
HGNC id 2195
Corresponding disease
KNO Knobloch syndrome
Location 21q22.3      Physical location : 46.825.096 - 46.933.633
Synonym name
  • endostatin
  • antiangiogenic agent
  • collagen alpha-1
  • multi-functional protein MFP
  • Synonym symbol(s) MEFP, MGC74745, FLJ27325, FLJ34914, KNO, KNO1, KS, EST
    DNA
    TYPE functioning gene
    STRUCTURE 108.54 kb     43 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Physical map
    IMMTP 21q22.3 inner membrane protein, mitochondrial (mitofilin) pseudogene KRTAP12-1 21q22.3 keratin associated protein 12-1 UBE2G2 21q22.3 ubiquitin-conjugating enzyme E2G 2 (UBC7 homolog, yeast) SMT3H1 21q22.3 SMT3 suppressor of mif two 3 homolog 1 (yeast) PTTG1IP 21q22.3 pituitary tumor-transforming 1 interacting protein ITGB2 21q22.3 integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit) C21orf69 21q22.3 chromosome 21 open reading frame 69 C21orf67 21q22.3 chromosome 21 open reading frame 67 C21orf70 21q22.3 chromosome 21 open reading frame 70 LOC391283 21 similar to interspersed repeat antigen, putative C21orf122 21q22.3 chromosome 21 open reading frame 122 ADARB1 21q22.3 adenosine deaminase, RNA-specific, B1 (RED1 homolog rat) C21orf89 21q22.1 chromosome 21 open reading frame 89 C21orf80 21q22.3 chromosome 21 open reading frame 80 C21orf86 21q22.1 chromosome 21 open reading frame 86 C21orf93 21q22.1 chromosome 21 open reading frame 93 LOC388830 21 similar to PRED59 COL18A1 21q22.3 collagen, type XVIII, alpha 1 LOC388831 21 LOC388831 SLC19A1 21q22.3 solute carrier family 19 (folate transporter), member 1 LOC388832 21 hypothetical gene supported by BC020585 LOC388833 21 LOC388833 PCBP3 21q22.3 poly(rC) binding protein 3
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    41 splicing 5910 153.8 1516 in liver, lung, spleen, skeletal muscle, thymus, kidney 1998 9503365
  • lacking exons1 and 2
  • having exon 3
  • 41 splicing 5398 - 1336 mainly in the kidney, but also in most of the other tissues including the retina 1998 9503365
    lacking exon 3
    41 splicing 6615 - 1751 exclusively in the liver 1998 9503365
  • same exon organization as variant 1
  • differing from variant 1 in using an alternative splice site in exon 9
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
    Cardiovascularvesselscapillary  highly
    Digestiveliver   highly
    Endocrinepancreas   highly
    Nervousbrain    
    Reproductivemale systemprostate   
    Respiratorylung   highly
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connective    
    Epithelialsecretoryglandularendocrine 
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
     epithelial cell
    Cardiovascularendothelial cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text neural tube, retina
    PROTEIN
    PHYSICAL PROPERTIES globular
    STRUCTURE
    motifs/domains
  • thrombospondin N-terminal-like domain with a zinc-binding site (its integrity is essential
  • for the stability and biological functions of endostatin)
  • ten interrupted triple helical domains
  • non triple helical regions with the 184 C terminal residues corresponding to endostatin
  • conjugated GlycoP
    mono polymer homomer , trimer
    isoforms Precursor precursor of endostatin (a potent antiangiogenic protein) which is proteolytically produced by the C-terminal fragment of type XVIII collagen
    HOMOLOGY
    interspecies homolog to murine Col18a1 (80.3pc)
    homolog to rattus Col18a1 (79.6pc)
    Homologene
    FAMILY
  • fibril-associated collagens with interrupted helices (FACIT) family
  • multiplexin collagen family
  • CATEGORY adhesion , structural protein
    SUBCELLULAR LOCALIZATION extracellular
    text
  • extracellular matrix, part of basement membrane molecular networks
  • colocalized with TGM2 in the extracellular matrix secreted by endothelial cells under hypoxia, which stimulates angiogenesis
  • basic FUNCTION
  • playing an important role in retinal structure, in eye organization and in neural tube closure
  • maintaining the structure of connective tissue
  • inhibiting endothelial cell proliferation (G(1) arrest) by down-regulation of the cyclin D1 promoter and angiogenesis (endostatin)
  • inhibiting angiogenesis by binding to the heparan sulphate proteoglycans and promoting formation of focal adhesion and actin stress fibers
  • involved in growth factor signaling
  • decreasing the hyperphosphorylated retinoblastoma gene product and down-regulating cyclin D1 mRNA and protein (endostatin)
  • playing an essential role for RPE function, and suggest an important role of this collagen in Bruch's membrane
  • endogenous inhibitor of angiogenesis, that inhibits proliferation and migration of endothelial cells
  • N-terminal integrity is very critical for its stability
  • and biological functions and expression systems make a huge difference with respect to the properties of endostatin
  • anti-angiogenic molecules, such as CNMD and COL18A1, have pivotal roles in preserving the avascularity of cartilage
  • promotes soft callus formation but inhibits callus remodeling during fracture healing most probably by an inhibition of angiogenesis
  • has a specific activity, independent of baseline synapse development, that is required for the homeostatic modulation of presynaptic calcium influx and neurotransmitter release
  • endogenous angiogenesis inhibitor with broad-spectrum antitumor activities
  • has novel ATPase activity, which mediates its antiangiogenic and antitumor activities
  • antiangiogenic factor, that is enriched in aging kidneys
  • kidney fibrosis in aging may represent a natural outcome of upregulated COL18A1 and TGM2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, COL18A1 and TGM2
  • CELLULAR PROCESS cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development
    text
  • histogenesis and organogenesis
  • negative control of cell proliferation
  • PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • Zn2+ binding
  • protein
  • binding to the heparan sulphate proteoglycans
  • binding to ITGA5 beta1 (to the inhibition of focal adhesion kinase MAP2K1, mitogen -activated protein kinase pathway)
  • endogenous angiogenesis inhibitor which requires E-selectin for its antiangiogenic activity
  • interacting with Integrin-heparan sulfate (may play a role in endostatin signaling by contributing to its localization to lipid rafts at the surface of endothelial cells) (Boniface 2009)
  • interacting with receptor nucleolin
  • interaction with TGM2 might participate in the concerted regulation of angiogenesis and tumorigenesis by COL18A1 and TGM2
  • cysteine cathepsins S and L modulate anti-angiogenic activities of COL18A1
  • interaction between COL18A1 short peptide and FLT4
  • COL18A1 is an interactive partner of transglutaminase 2 (TGM2), an enzyme that cross-links extracellular matrix proteins
  • cell & other
    REGULATION
    Other excess of the COL18A1 Tsp-1 domain is deleterious in the eye, possibly by impairing certain functions of the full-length molecule
    ASSOCIATED DISORDERS
    corresponding disease(s) KNO
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in primary Sjögren syndrome, particularly in those with interstitial lung disease (ILD)
    Susceptibility to age-related macular degeneration
    Variant & Polymorphism other
  • polymorphism at position 1437 in prostate cancer (heterozygous Asn-1437 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous Asp-1437 individuals)
  • allele N104 for the endostatin domain represent a modifier allele for disorder in which angiogenesis is important, such a cancer
  • SNP in COL18A1 are associated with hepatopulmonary syndrome
  • Candidate gene
  • high expression is associated with poor prognosis in patients with metastatic carcinoma
  • Marker
  • serum COL18A1 as a potential biomarker in
  • Pulmonary arterial hypertension (PAH) with the capacity to predict poor outcomes
    Therapy target
    SystemTypeDisorderPubmed
    cancerangiogenesis 
    construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs
    neurosensorialvisual 
    therapeutic up-regulation may be a new strategy in the treatment of neovascular AMD (age-related macular degeneration)
    respiratorylung 
    COL18A1/ES is a potential new therapeutic target in Pulmonary arterial hypertension (PAH)
    miscelleaneoushypertension 
    coadministration of COL18A1 with VEGFA inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression
    ANIMAL & CELL MODELS
  • Collagen XVIII deficiency leads to anterior and posterior eye defects in Col18a1(-/-) mice
  • Col18a1(-/-) mice showed effacement of the glomerular podocyte foot processes, and microindentation studies showed changes in the mechanical properties of the glomeruli