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A2M (alpha-2-macroglobulin)

Written2020-04Rafig Gurbanov, Gizem Samgane
Department of Molecular Biology and Genetics (RG) and Department of Biotechnology (GS) Bilecik Seyh Edebali University, Bilecik Seyh Edebali University, Biotechnology Application and Research Center, Turkey. rafig.gurbanov@bilecik.edu.tr; gsamgane@gmail.com

Abstract Alpha-2-Macroglobulin (A2M) was first recognized as a broad-spectrum protease inhibitor and is a pan-proteinase inhibitor that can mechanistically inhibit all proteinase families. It plays an important role in the clearance of proteinases from circulation, regulation of fibrinolysis, coagulation and complement activation. A2M is also known to act as a transport/carrier protein. In general, A2M is produced by the liver as an acute-phase protein during stress conditions and then secreted into the blood and extracellular environments where it functions. It is also locally produced by macrophages, fibroblasts, and epithelial cells. A2M gene mutations play a role in the pathogenesis of diseases such as Alzheimer's disease, parkinson's disease, and prostate cancer.

Keywords Alpha-2-Macroglobulin (A2M), Pan-proteinase inhibitor, Alzheimer Disease, Parkinson's Disease

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)FWP007
S863-7
CPAMD5
Other aliasAlpha-2-Macroglobulin
C3 And PZP-Like Alpha-2-Macroglobulin Domain-Containing Protein 5
Alpha-2-M
A2MD 
HGNC (Hugo) A2M
LocusID (NCBI) 2
Atlas_Id 42923
Location 12p13.31 [Link to chromosome band 12p13]  [Link to chromosome band 12p13]
Location_base_pair Starts at 9067708 and ends at 9115919 bp from pter ( according to hg19-Feb_2009)  [Mapping A2M.png]
Local_order shown in Chromosome 12 - NM_001347425 (GRCh38.p13 Primary Assembly).
 
  Figure 1. Genomic location of A2M (Chromosome 12 - NM_001347425 (GRCh38.p13 Primary Assembly).
 
  Figure 2. Chromosomal Location of A2M (https://www.genecards.org/). Cytogenetic Location of A2M: 12p13.31, which is the short (p) arm of chromosome 12 at a position 13.31 (UCSC Genome Browser on Human Dec. 2013 (GRCh38/hg38) Assembly).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note The A2M gene is 48.446 bp long (according to UCSC, GRCh38/hg38), located on the minus (-) strand and spans 37 exons (NCBI Homo sapiens Annotation Release 109).
 
  Figure 3. Numbers and illustrative sizes of exons of human A2M. (http://atlasgeneticsoncology.org/)
Transcription The gene has 13 transcripts (Table 1)
Table 1. Transcripts of the human A2M gene (Ensemble, GRCh38.p12).
Name Transcript ID bpProtein (aa)Biotype
A2M-201ENST00000318602.1148441474aaProtein coding
A2M-202ENST00000404455.2623168aaProtein coding
A2M-213ENST00000546069.159373aaNonsense mediated decay
A2M-209ENST00000539638.559090aaNonsense mediated decay
A2M-211ENST00000543436.2600No proteinProcessed transcript
A2M-210ENST00000542567.1563No proteinProcessed transcript
A2M-204ENST00000467091.1533No proteinProcessed transcript
A2M-208ENST00000497324.1533No proteinProcessed transcript
A2M-212ENST00000545828.1471No proteinProcessed transcript
A2M-206ENST00000495442.1729No proteinRetained intron
A2M-205ENST00000472360.1692No proteinRetained intron
A2M-203ENST00000462568.1546No proteinRetained intron
A2M-207ENST00000495709.1509No proteinRetained intron
Pseudogene A related pseudogene so-called Alpha-2-macroglobulin pseudogene 1 (A2MP1) with 9 exons has been identified in chromosome 12p13.31.

Protein

Note Alpha-2-Macroglobulin (A2M) is a protein-coding gene (https://www.genecards.org/cgi-bin/carddisp.pl?gene=A2M&keywords=A2M). The human A2M is a 720 kDa soluble glycoprotein composed of four identical 180 kDa (1451 amino acid) subunits, each of which is encoded by a single-copy gene on chromosome 12 (Kovacs, 2000). A2M protein is a plasma proteinase inhibitor and binds with the amyloid beta peptide (A beta) specifically and preserves the A beta peptides in a soluble condition, preventing fibril formation (Zamani et al., 2016). The protein encoded by this gene is a protease inhibitor and cytokine transporter (https://www.genecards.org/cgi-bin/carddisp.pl?gene=A2M&keywords=A2M). It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin, and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades (https://www.ncbi.nlm.nih.gov/gene/2). This protein has a peptide stretch, called the bait region which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates whereas the activity against high molecular weight substrates is greatly reduced. Following cleavage in the bait region, a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase (https://www.uniprot.org/uniprot/P01023). Similar to other alpha-macroglobulins such as complement components C3 and C4A and the PZP (PZP alpha-2-macroglobulin like), A2M has an extraordinary binding capacity for a variety of ligands. In the plasma, this allows the alpha-macroglobulins to function as defense barriers against foreign peptides (Kovacs, 2000).
Expression A2M gene is most commonly expressed in endocrine tissues, lung, liver and gallbladder, female tissues, and adipose and soft tissues. It is less expressed in the eye, pancreas, and blood.
 
  Figure 4. Expression profile of A2M in different tissues/organs in women and men
Localisation A2M is found in various cellular compartments such as extracellular region, extracellular space, cytosol, platelet alpha granule lumen, collagen-containing extracellular matrix, extracellular exosome, blood microparticle (https://www.ensembl.org/index.html).
 
  Figure 5. Structure of A2M protein (https://www.rcsb.org/).
Function Human A2M is a homotetrameric plasma glycoprotein consisting of polypeptide chains of 720-kDa and 1451 residues (Doan and Gettins, 2007; Arandjelovic et al., 2007). A2M, the largest known proteinase inhibitor (Mr = 720,000), is present in high concentrations (2-5 μM) in plasma and extravascular areas (Krimbou et al., 2001). A2M was first recognized as a broad-spectrum protease inhibitor and is a pan-proteinase inhibitor that can mechanistically inhibit all proteinases (Arandjelovic et al., 2007; French et al., 2008). In addition, it can strongly but non-covalently and reversibly bind to several growth factors. Proteolytic cleavage of the bait region by bait proteinase leads to major conformational changes, resulting in proteinase compression. The bait region is a stretch consisting of roughly 30 residues located approximately in the middle of the polypeptide chain; it is a flexible region with many residue types giving a broad spectrum of cleavage sites (Doan and Gettins, 2007). It plays an important role in the clearance of proteinases from circulation, regulation of fibrinolysis, coagulation and complement activation (Krimbou et al., 2001). A2M is also known to act as a transport/carrier protein because it also binds to numerous growth factors and specific cytokines (Kim et al., 2018; Wyatt et al., 2014). A2M also transports numerous non-proteolytic proteins including APOE (apolipoprotein E) (Krimbou et al., 2001). A2M interacts with proteinases such as KLK (kallikrein), PLG (plasminogen), MMP2 (matrix metallopeptidase 2), and MMP9 (matrix metallopeptidase 9). In general, A2M is produced by the liver as an acute-phase protein during stress conditions and then secreted into the blood and extracellular environments where it functions. It is also locally produced by macrophages, fibroblasts and epithelial cells (Kim et al., 2018). Being a unique pan-protease inhibitor, A2M is also synthesized and secreted in the brain (Bacskai et al., 2000). It can induce cell signalling by binding to the LRP1 (LDL receptor related protein 1) and/or other cell surface receptors (Arandjelovic et al., 2006). A tetrameric complex undergoes a conformational change when a bait region is separated by a protease. This both sterically traps the protease and then produces an active form of A2M (A2M*), which is a ligand for LRP1. Methylamine (ammonium derivative) administration causes the exact conformational change and is used experimentally to produce A2M*. LRP1 and LRP8 are the brain receptors for A2M*, which mediate clearance of protease/protease inhibitor complexes (Bacskai et al., 2000).
 
  Figure 6. The implication of A2M in coagulation and complement systems. A2M can neutralize a massive variety of proteinases (including serine, cysteine-, aspartic-, and metalloproteinases). It acts as an inhibitor of fibrinolysis by inhibiting PLG and KLK, and as a coagulation inhibitor by inhibiting F2 (coagulation factor II /thrombin). Data were taken from KEGG: Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg/) in April 2020.
Homology The A2M gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog (Table 2).
Table 2. Pairwise alignment of A2M gene protein sequences (in distance from humans) (HomoloGene, NCBI).
GeneIdentity (%)
SpeciesSymbolProtein DNA
H.sapiensA2M  
vs. P.troglodytesA2M99.2 
vs. M.mulattaA2M94.996.4
vs. C.lupusA2M80.684.7
vs. B.taurusA2M79.383.5
vs. M.musculusA2M73.478.2
vs. R.norvegicusA2M74.878.4
vs. R.norvegicusLOC10091154574.878.4
vs. G.gallusA2M59.764.2
vs. X.tropicalisLOC10048906051.557.0
vs. X.tropicalisa2m52.257.3
vs. D.rerioLOC10000378541.251.3
vs. D.rerioLOC10000678242.151.9
vs. D.rerioLOC10000689541.651.7
vs. D.rerioLOC10000692544.653.9
vs. D.rerioa2ml41.451.6
vs. D.rerioa2ml40.850.2
vs. D.reriosb:cb3741.351.8
vs. D.reriosi:dkey-46g23.238.949.4
vs. D.reriosi:dkey-46g23.539.049.5
vs. D.reriosi:dkey-52d15.240.051.4
vs. D.reriozgc:16545337.949.6
vs. D.reriozgc:16551838.549.7
vs. D.reriozgc:17142638.949.7
vs. D.reriozgc:17144537.448.7
vs. D.reriozgc:17144638.349.2

Mutations

Note The most common type of mutation in the A2M gene is the missense/nonsense mutation, and there are 4 mutations in this category. In addition, 1 small deletion mutation and 1 splicing mutation type are seen. These mutations lead to the clinical manifestation of diseases such as Alzheimer's Disease (AD) (Saunders 2003; Liao 1998; Blacker 1998), Chronic Obstructive Pulmonary Disease (COPD) (Poller 1992), and Autism Spectrum Disorder (ASD) (Sanders 2012) (Table 3).
Table 3. A2M related mutations.
Missense/nonsense: 4 mutations
HGMD accesionHGMD codon changeHGMD amino acid changeHGVS (nucleotide)HGVS (protein)Variant classReported phenotypeReference
CM032792TAC-TATTyr432Tyrc.1296C>Tp.Y432=DPAlzheimer disease, association withSaunders (2003) Hum Mol Genet 12, 2765
CM920001TGT-TATCys972Tyrc.2915G>Ap.C972YDM?Chronic obstructive pulmonary diseasePoller (1992) Hum Genet 88, 313
CM980001GTC-ATCVal1000Ilec.2998G>Ap.V1000IDPAlzheimer disease, association withLiao (1998) Hum Mol Genet 7, 1953
CM124419CGC-TGCArg1297Cysc.3889C>Tp.R1297CDM?AutismSanders (2012) Nature 485, 237
        
Small deletions: 1 mutation
HGMD accesionHGMD deletionHGMD amino acid changeHGVS (nucleotide)HGVS (protein)Variant classReported phenotypeReference
CD984159TTCCTCACTaccatAG_I17E18_AG^710TCAGATNot yet availablec.2126-6_2126-2delCCATANot yet availableDPAlzheimer disease, association withBlacker (1998) Nat Genet 19, 357
Splicing: 1 mutation
HGMD accesionHGMD splicing mutationHGMD amino acid changeHGVS (nucleotide)HGVS (protein)Variant classReported phenotypeReference
CS033097IVS20 as T-A -4Not yet availablec.2597-4T>ANot yet availableDPAlzheimer disease, association withSaunders 2003) Hum Mol Genet 12, 2766

Implicated in

Note A2M protein has been reported to bind pro-inflammatory cytokines, TNF (tumor necrosis factor) and IL1A (interleukin 1 alpha), which play a central role in the pathogenesis of chronic inflammatory disorders, including Inflammatory Bowel Disease (IBD) and Rheumatoid Arthritis (RA). (Webb et al., 1998).
Animal Studies
Umans et al. (1995) created mice lacking the A2M gene, which was viable, more resistant to endotoxins, produced normal litters, and demonstrated normal phenotype (Umans et al., 1995). Webb et al. (1996) showed that murine A2M binds TGFB1 (tumor growth factor beta 1) and inhibits TGFB-receptor interactions, suggesting that these results explain the endotoxin-insensitive phenotype of knockout mice (Webb et al., 1996). Zhang et al. (2017) evaluated whether the targeted A2M variants have an improved or similar function to wild-type (wt) A2M to alleviate cartilage degeneration in vivo. They observed that the targeted variants of A2M had a close chondroprotective effect with wt-A2M (Zhang et al., 2017). Cancer resistance is an important reason for the longevity of the naked mole-rat (Kurz et al., 2017). Recent liver transcriptome analysis revealed higher expressions of A2M and other cell adhesion molecules in naked mole-rat compared to wild mice that contribute to cancer resistance (Kurz et al., 2017). It is known that A2M decreases significantly in humans with age. Therefore, it is assumed that this event may facilitate tumor development. Upon this assumption, it was shown that A2M* modulates tumor cell adhesion, migration, and growth by inhibiting tumor-promoting signaling pathways, such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and small mother against decapentaplegic (SMAD) (Kurz et al., 2017). A2M* upregulates the expressions of tumor suppressor PTEN (phosphatase and tensin homolog), ITGB1 (integrin subunit beta 1), and CD44 but does not evoke epithelial-mesenchymal-transition (EMT) events (Kurz et al., 2017).
  
Entity Prostate Cancer
Note Prostate Cancer (PCa) cells produce a high level of differentiation marker for KLK3 (kallikrein related peptidase 3), just like normal prostate epithelial cells (Cumming et al., 2011). KLK3 is widely used as a biomarker to screen for PCa, to detect recurrence following local treatments, and to track response to systemic treatments in metastasis (Cumming et al., 2011; Kostova et al., 2018). Some studies have suggested that KLK3 may play a role in PCa pathology through various mechanisms, including changes in the invasive abilities of the PCa cell, gene expression, and morphology (Kostova et al., 2018). KLK3 has a serine protease chymotrypsin-like enzymatic activity and is a member of the glandular kallikrein family (Ezenwa et al., 2012). It has been shown that A2M and KLK3 can form a complex (Ezenwa et al., 2012; Stephan et al., 2014). A2M is the most abundant protease inhibitor in the blood also inhibiting many protease activities related to fibrinolytic action and inflammatory reactions. (Kanoh et al., 2008; Kanoh et al., 2011; Kanoh et al., 2012). It has also been reported that A2M can inhibit the activity of proteases and thus can inhibit the ability of cancers to infiltrate and metastasize (Kanoh et al., 2008; Kanoh et al., 2011; Kanoh et al., 2012). Compared with other protease inhibitors, KLK3 more easily reacts with A2M than in plasma (Kanoh et al., 2008; Kanoh et al., 2011; Kanoh et al., 2012). Serum KLK3 levels of PCa patients with A2M deficiency were significantly higher than PCa patients without A2M deficiency (Kanoh et al., 2008). The ratios of free KLK3 to total KLK3 (F/T ratios) of PCa patients with A2M deficiency were significantly lower than PCa patients without A2M deficiency. Therefore, patients with advanced PCa appear likely to have multiple bone metastases and increased serum KLK3 with A2M deficiency (Kanoh et al., 2008). On the other hand, serum A2M levels tend to decrease with the progression of PCa. In cases where serum KLK3 levels showed dramatic increases (>2,000 mg/dl), serum A2M levels tended to drop significantly (<20 mg/dl). The decrease in serum A2M levels may be brought about by the reticuloendothelial system rapidly removing many A2M-KLK3 complexes from the blood in PCa patients with extremely high levels of serum KLK3 (Kanoh et al., 2008). Furthermore, the genetic analysis of one patient with A2M deficiency showed no mutation in the A2M gene. These results suggest that A2M deficiency develops from the A2M catabolism in patients with androgen-dependent advanced PCa and serum A2M levels may be an indicator of disease progression in addition to KLK3 levels (Kanoh et al., 2012).
  
  
Entity Acute Lymphoblastic Leukemia
Note Many studies have shown coagulation and/or fibrinolysis abnormalities in approximately 50% of malignant patients and over 90% of those who have developed metastases. (Kwon et al., 2008; Bick, 1992; Luzzatto and Schafer, 1990; Hillen, 2000). The expression levels of A2M associated with fibrinolysis have been shown to increase differently in bone marrow plasma samples of acute lymphoblastic leukemia (ALL) patients (Braoudaki et al., 2013). A2M protein was three-fold upregulated in the serum of B cell-ALL patients, and its level of expression decreased significantly after induction therapy (Cavalcante et al., 2016). However, compared with serum samples from control patients, no significant changes in expression levels of A2M were observed. Therefore, A2M can be considered as a candidate biomarker of B cell-ALL and for evaluation of the response to induction therapy in patients (Cavalcante et al., 2016). A recent study also identified A2M as a candidate biomarker for the diagnosis of B-cell ALL by serum proteomic analysis (Guo et al., 2019).
  
  
Entity Fetal Lung Interstitial Tumor
Note Fetal Lung Interstitial Tumor (FLIT) is very rare (Onoda et al., 2014) and an infantile pulmonary lesion that occurs predominantly in newborns (Tanaka et al., 2017). Onoda et al. (2014) characterized a novel chromosomal rearrangement resulting in A2M and ALK (ALK receptor tyrosine kinase) gene fusion in a patient with FLIT (Onoda et al., 2014). The corresponding chimeric gene was subsequently confirmed by sequencing, including the genomic breakpoint between intron 22 and 18 of A2M and ALK, respectively. The Discovery of A2M as a novel ALK fusion partner, together with the involvement of ALK, provides new insights into the pathogenesis of FLIT and suggests the potential for new therapeutic strategies based on ALK inhibitors (Onoda et al., 2014). Tanaka et al. (2017) suggested that these infantile pulmonary lesions containing a chimeric A2M/ALK gene should be categorized as a specific type of inflammatory myofibroblastic tumor that develops only in newborns and infants (Tanaka et al., 2017).
  
  
Entity Alzheimer's Disease
Note Human studies suggest that A2M may have a key role in neuroinflammatory response to AD pathogenesis (Varma et al., 2017). This evidence includes the co-localization of A2M with amyloid plaques and proteomic studies with increased plasma A2M concentration in AD patients compared to controls (Bauer et al., 1991; Thal et al., 1997). AD is characterized by the formation of senile plaques and neurofibrillary nodes in the brain (Selkoe and Hardy, 2016; Yuan et al., 2013). Since A beta is the main component of senile plaques, the genes encoding proteins implicated in the A beta clearance (LRP1 and A2M) were proposed as risk factors for AD and Sporadic Alzheimer's disease (SAD) (Yuan et al., 2013). A2M is a serum pan-protease inhibitor in AD, based on its ability to mediate clearance and disruption of A beta through the primary neuronal LRP1 for APOE (Blacker et al., 1998; Cater et al., 2019). Due to its roles in APOE and APP (amyloid beta precursor protein) metabolism in the brain, A2M and is considered a risk factor for AD (Zill et al., 2000).
It has been demonstrated that the incidence of A2M GG genotype in AD (8.1%) is more frequent than control groups (3.79%) and that homozygous A2M deletion (A2M DD) did not occur in control groups, but was observed in 5.21% of AD patients (Cacabelos, 2002). According to some studies, the A2M gene has two polymorphisms associated with AD independent from the APOE status (Zill et al., 2000; Poduslo et al., 2002). The first polymorphism that is a 5-base pair (bp) deletion in the 5' splice site of exon 18 resulting in exon skipping was found to be associated with the AD (Zill et al., 2000; Poduslo et al., 2002). The second polymorphism is a G>A point mutation (Zill et al., 2000) in exon 24 that leads to a Valin to Isoleucine exchange (Val1000Ile). It has been suggested that Val1000Ile polymorphism alters protein function as it occurs near the thioester region of the protein (Zill et al., 2000). This polymorphism has been reported to be associated with the late-onset AD form of the homozygous G allele, but other studies have not confirmed these results (Zill et al., 2000; Yuan et al., 2013).
Plasma A2M concentration is significantly associated with cerebrospinal fluid (CSF) markers of neuronal damage, which are total-tau and phosphorylated tau proteins (Seddighi et al., 2018). It has also been found that higher A2M concentration in basal serums of cognitively normal individuals is associated with greater risk of progression to clinical AD in men, indicating a gender-specific change in the inflammatory response in the early stages of AD pathogenesis (Seddighi et al., 2018).
A2M gene and protein expressions in the brain were found to be significantly associated with the gene and protein expression levels of CAMK2B (calcium/calmodulin dependent protein kinase II beta), which is a well-characterized tau phosphatase so called calcineurin. By using a system-level approach that combines multiple tissue gene expression datasets with mass spectrometry-based proteomic analysis of brain tissue, the A2M gene network containing a RCAN1 (regulator of calcineurin 1), has been identified (Varma et al., 2017). These findings suggest that A2M is also associated with preclinical AD, reflecting early neuronal damage in the course of the disease and may respond to tau phosphorylation in the brain through RCAN1 and CAMK2B (Varma et al., 2017).
  
  
Entity Parkinson's disease
Note A2M is a component of Lewy bodies (LB), associated with a hallmark of Parkinson's Disease (PD) (Krüger et al., 2000). It has been reported that A2M can regulate proteolytic events in LB formation (Krüger et al., 2000). AG transition (rs669) at codon 1000 near the thioester region and 5 bp deletion (rs3832852) adjacent to the splice site at intron 17 in the A2M gene have been shown to transform the A2M protein structure and alter the protein function (Poller et al., 1992). Given the biological function of A2M in protein accumulation, some studies have investigated the relationships between A2M gene polymorphisms and PD risk (Benitez et al., 2010). Some studies have suggested that rs669 single nucleotide polymorphism (SNP) is associated with an increased risk of PD (Tang et al., 2002; Xiao and Zhang, 2006). However, in some studies, no relation was found between A2M polymorphisms and PD (Nicoletti et al., 2002). In a meta-analysis study investigating the relationship between rs669 and rs3832852 polymorphisms with PD risk, a total of 877 PD patients and 1296 controls from six studies were included (Guo et al., 2016). Odds ratio (OR) showed that rs669 polymorphisms were probably associated with increased PD risk only in dominant genetic models (OR = 1.41, CI = 1.03-1.92), especially in the Asian subgroup (OR = 1.97, CI = 1.03-3.75). Krüger et al. (2000) conducted a genetic study in a large sample of 328 German PD patients and 322 closely matched healthy controls (Krüger et al., 2000). By analyzing Val1000Ile polymorphism and a 5 bp deletion in the 5' splice region of exon 18, they observed excess of homozygosity for the A2M deletion in early-onset PD patients (age at onset <50 years) compared to late-onset PD patients (age at onset> 50 years) (Krüger et al., 2000).
  
  
Entity Hepatic Fibrosis
Note A2M is a well-known biomarker of hepatic fibrosis (HF) (Naveau et al., 1994; Calès et al., 2005; Ho et al., 2010). In the inflammatory or injured liver, increased A2M inhibits the catabolism of matrix proteins and thus causes HF (Tiggelman et al., 1996; Ho et al., 2010). While A2M binds to fibrinolytic enzymes, it cleaves at its thioester region (Rehman et al., 2013). The thioester cleavage may increase with HF development. Compared to healthy control serum, the thioester cleaved C-terminal end of A2M was found to change by more than two-fold in percentage spot volume only in cirrhotic serum analysed by 2D gel electrophoresis. The thioester-cleaved N-terminal end of A2M changed by more than two-fold mostly in cirrhotic serum and with fewer glycoforms in the serum of moderate HF patients. Uncleaved A2M was differentially expressed in all stages of HF. However further analysis of the thioester cleavage products may give a more reliable indication of HF activity (Gangadharan et al., 2007).
  
  
Entity Osteonecrosis of Femoral Head
Note Diagnosis of Osteonecrosis of Femoral Head (ONFH) is complex due to the lack of reliable serum biomarkers (Ghale-Noie et al., 2018). The upregulation of the A2M gene has been reported in the glucocorticoid (GC)-induced ONFH rat model (Ghale-Noie et al., 2018). It has been suggested that A2M serum level is suitable as an indicative biomarker for glucocorticoid GC-induced ONFH in rodents and A2M may play a role in host repair response to GC-related effects (Carli et al., 2017). According to Fang et al. (2019), A2M can be associated with Steroid-induced Necrosis of Femoral Head (SINFH) (Fang et al., 2019). Multiple pathological reactions occurring in SINFH and A2M can serve as a potential biomarker for SINFH diagnosis or a promising therapeutic target (Fang et al., 2019). The ONFH presumably directly or indirectly elevates A2M in the bloodstream. Therefore, the serum level of A2M might be used as a reliable diagnostic tool in clinical practice (Ghale-Noie et al., 2018). 
  
  
Entity Rheumatoid Arthritis
Note Inflammation is important in the pathogenesis of arthritis (Li et al., 2019). Early administration of intra-articular A2M may provide chondral protection in RA by reducing the presence of local catabolic proteases and inflammation levels (Li et al., 2019). The intra-articular A2M administration induced an anti-inflammatory response and slowed cartilage damage and bone resorption, suggesting that supplemental A2M may be a novel therapy for arthritis (Li et al., 2019). In a study where potential serum biomarkers for RA were determined by high resolution quantitative proteomic analysis, A2M protein was observed to be downregulated (Cheng et al., 2014). In the hospital-based case-control study conducted on the South Asian (134 RA cases, 149 controls) and Caucasian (137 RA cases, 150 controls) populations, the 5 bp deletion polymorphism of the A2M gene was examined (Ghelani et al., 2011). It was reported that the A2M locus shows an ethnically specific variation and maybe a useful marker for RA (Ghelani et al., 2011). A2M can inhibit the MMPs (matrix metalloproteinases), which are elevated in many chronic inflammatory diseases such as RA, and is considered as a potential inflammatory biomarker of MMP activity and RA (Wedekind et al.,2017).
  
  
Entity Osteoarthritis
Note Osteoarthritis (OA) is an age-related and chronic degenerative disease that is characterized by the degradation of the extracellular matrix (ECM) of chondrocytes (Liu et al., 2019). It has been shown that A2M levels are lower in synovial fluid from patients with OA, and additional A2M injection reduces the progression of post-traumatic OA in rats (Wang et al., 2014). Synovial fluids of OA patients do not include the A2M levels required to inactivate the high concentrations of catabolic factors and the additional intraarticular A2M provides chondral protection in post-traumatic OA. Increasing evidence in this context showed that A2M is the most effective factor for cartilage protection as an active anti-inflammatory component of the platelet-rich plasma (PRP) injections (Orhurhu et al., 2020).
  
  
Entity Chronic Obstructive Pulmonary Disease
Note A2M is speculated to play a role in regulating protease activity in the lung (Poller et al., 1989). The most common variation of the A2M gene is 5 bp deletion (Dimov and Vlaykova, 2010). Though rare, hereditary A2M deficiency has been associated with 20-30 times higher risk of COPD (Dimov and Vlaykova, 2010). The increased plasma concentrations of A2M was detected in smoking and non-smoking patients with COPD (96 individuals) compared to healthy controls (33 individuals) (Arellano-Orden et al., 2017). It was recently determined that the interactions of MiR-122-5p-A2M-LINC00987 / A2M-AS1 / linc0061 networks may play a key role in COPD irrespective of the smoking status. Moreover, A2M was suggested as a potential biomarker of COPD (Qian et al., 2018).
  
  
Entity Inflammatory Bowel Disease
Note IBD comprises a group of disorders characterized by chronic intestinal inflammation with the main phenotypes being Crohn's Disease (CD) and Ulcerative Colitis (UC) (Hansen et al., 2012). Proteases and protease inhibitors have considerable implications in IBD because of their contributions to the mucosal barrier function of the gut (Cleynen et al., 2011). The systematic review study presented the A2M as one of the top genes implicated in UC (Cleynen et al., 2011). It was observed that serum A2M protein amount decreased by 0.5-fold in IBD patients compared to non-IBD controls (Knutson et al., 2013). Recently, the divergent plasma concentrations of A2M protein have been identified in both subtypes (CD and UC) of IBD compared to controls (Di Narzo et al, 2019). In another study, 7668 peptides were analyzed to distinguish between stricturing CD and non-stricturing CD, in which only 16 peptides including A2M were found to be involved (Townsend et al., 2015).
  
  
Entity Autism Spectrum Disorder
Note Previously whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, revealed highly disruptive de novo mutations in brain-expressed genes associated with ASD (Sanders et al., 2012). A2M gene was proposed as a risk factor with damaging severity score for transcript variant 1 (NM_000014) ASD (Sanders et al., 2012). A relationship between transposable element content and autism-risk genes including the A2M gene has also been shown (Williams et al., 2013). Moreover, the subjects with ASD exhibited a significantly higher expression level of the A2M (Cortelazzo et al., 2016; Abraham et al., 2019). Furthermore, A2M was associated with complement and coagulation cascades, indicating that these systems may be involved in the pathogenesis of ASD (Shen et al., 2019).
  

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Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices
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Alpha-2 macroglobulin is genetically associated with Alzheimer disease
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Substrain-specific differences in bone parameters, alpha-2-macroglobulin circulating levels, and osteonecrosis incidence in a rat model
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J Orthop Res 2017 Jun;35(6):1183-1194
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Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator
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Expression and oxidative modifications of plasma proteins in autism spectrum disorders: Interplay between inflammatory response and lipid peroxidation
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PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo
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High-Throughput Identification of the Plasma Proteomic Signature of Inflammatory Bowel Disease
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Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3
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0-10 0 ng/mL) in Nigeria
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Thrombosis in cancer patients
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J Biomed Sci 2010 Jul 15;17:58
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Clinicopathological characteristics of androgen-dependent advanced prostate cancer patients with α2-macroglobulin deficiency
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MMP2-A2M interaction increases ECM accumulation in aged rat kidney and its modulation by calorie restriction
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Proc Natl Acad Sci U S A 2013 Jun 25;110(26):E2332-41
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PSA-alpha-2-macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones
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Prostate 2018 Aug;78(11):819-829
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alpha2-macroglobulin in late-onset Alzheimer's disease
Kovacs DM
Exp Gerontol 2000 Jul;35(4):473-9
PMID 10959035
 
Genetic analysis of the alpha2-macroglobulin gene in early- and late-onset Parkinson's disease
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Neuroreport 2000 Aug 3;11(11):2439-42
PMID 10943700
 
Interaction of lecithin:cholesterol acyltransferase (LCAT)
Krimbou L, Marcil M, Davignon J, Genest J Jr
alpha 2-macroglobulin complex with low density lipoprotein receptor-related protein (LRP) Evidence for an alpha 2-macroglobulin/LRP receptor-mediated system participating in LCAT clearance
PMID 11435418
 
The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat
Kurz S, Thieme R, Amberg R, Groth M, Jahnke HG, Pieroh P, Horn LC, Kolb M, Huse K, Platzer M, Volke D, Dehghani F, Buzdin A, Engel K, Robitzki A, Hoffmann R, Gockel I, Birkenmeier G
PLoS One 2017 Dec 27;12(12):e0189514
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Plasma levels of prothrombin fragment F1+2, D-dimer and prothrombin time correlate with clinical stage and lymph node metastasis in operable gastric cancer patients
Kwon HC, Oh SY, Lee S, Kim SH, Han JY, Koh RY, Kim MC, Kim HJ
Jpn J Clin Oncol 2008 Jan;38(1):2-7
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Early supplemental α2-macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II-induced arthritis model
Li S, Xiang C, Wei X, Sun X, Li R, Li P, Sun J, Wei D, Chen Y, Zhang Y, Wei L
Int J Rheum Dis 2019 Apr;22(4):654-665
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Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease
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Hum Mol Genet 1998 Nov;7(12):1953-6
PMID 9811940
 
MiR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin
Liu X, Liu L, Zhang H, Shao Y, Chen Z, Feng X, Fang H, Zhao C, Pan J, Zhang H, Zeng C, Cai D
Aging (Albany NY) 2019 Aug 17;11(16):6014-6028
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The prethrombotic state in cancer
Luzzatto G, Schafer AI
Semin Oncol 1990 Apr;17(2):147-59
PMID 2183357
 
Alpha-2-macroglobulin and hepatic fibrosis
Naveau S, Poynard T, Benattar C, Bedossa P, Chaput JC
Diagnostic interest Dig Dis Sci
PMID 7525168
 
No evidence of association between the alpha-2 macroglobulin gene and Parkinson's disease in a case-control sample
Nicoletti G, Annesi G, Tomaino C, Spadafora P, Pasqua AA, Annesi F, Serra P, Caracciolo M, Messina D, Zappia M, Quattrone A
Neurosci Lett 2002 Aug 2;328(1):65-7
PMID 12123860
 
Identification of novel ALK rearrangement A2M-ALK in a neonate with fetal lung interstitial tumor
Onoda T, Kanno M, Sato H, Takahashi N, Izumino H, Ohta H, Emura T, Katoh H, Ohizumi H, Ohtake H, Asao H, Dehner LP, Hill AD, Hayasaka K, Mitsui T
Genes Chromosomes Cancer 2014 Oct;53(10):865-74
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Role of Alpha-2-Microglobulin in the Treatment of Osteoarthritic Knee Pain: a Brief Review of the Literature
Orhurhu V, Schwartz R, Potts J, Peck J, Urits I, Orhurhu MS, Odonkor C, Viswanath O, Kaye A, Gill J
Curr Pain Headache Rep 2019 Sep 9;23(11):82
PMID 31502073
 
Lack of association of the two polymorphisms in alpha-2 macroglobulin with Alzheimer disease
Poduslo SE, Shook B, Drigalenko E, Yin X
Am J Med Genet 2002 Jun 1;110(1):30-5
PMID 12116268
 
Detection of an alteration of the alpha 2-macroglobulin gene in a patient with chronic lung disease and serum alpha 2-macroglobulin deficiency
Poller W, Barth J, Voss B
Hum Genet 1989 Aug;83(1):93-6
PMID 2475424
 
Cloning of the human alpha 2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site
Poller W, Faber JP, Klobeck G, Olek K
Hum Genet 1992 Jan;88(3):313-9
PMID 1370808
 
Comprehensive Analysis of miRNA-mRNA-lncRNA Networks in Non-Smoking and Smoking Patients with Chronic Obstructive Pulmonary Disease
Qian Y, Mao ZD, Shi YJ, Liu ZG, Cao Q, Zhang Q
Cell Physiol Biochem 2018;50(3):1140-1153
PMID 30355907
 
α-2-Macroglobulin: a physiological guardian
Rehman AA, Ahsan H, Khan FH
J Cell Physiol 2013 Aug;228(8):1665-75
PMID 23086799
 
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW
Nature 2012 Apr 4;485(7397):237-41
PMID 22495306
 
Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin
Saunders AJ, Bertram L, Mullin K, Sampson AJ, Latifzai K, Basu S, Jones J, Kinney D, MacKenzie-Ingano L, Yu S, Albert MS, Moscarillo TJ, Go RC, Bassett SS, Daly MJ, Laird NM, Wang X, Velicelebi G, Wagner SL, Becker DK, Tanzi RE, Blacker D
Hum Mol Genet 2003 Nov 1;12(21):2765-76
PMID 12966032
 
α2-macroglobulin in Alzheimer's disease: new roles for an old chaperone
Seddighi S, Varma V, Thambisetty M
Biomark Med 2018 Apr;12(4):311-314
PMID 29537301
 
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe DJ, Hardy J
EMBO Mol Med 2016 Jun 1;8(6):595-608
PMID 27025652
 
Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children
Shen L, Feng C, Zhang K, Chen Y, Gao Y, Ke J, Chen X, Lin J, Li C, Iqbal J, Zhao Y, Wang W
Front Cell Neurosci 2019 Mar 19;13:105
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Prostate-specific antigen and other serum and urine markers in prostate cancer
Stephan C, Ralla B, Jung K
Biochim Biophys Acta 2014 Aug;1846(1):99-112
PMID 24727384
 
Inflammatory myofibroblastic tumors of the lung carrying a chimeric A2M-ALK gene: report of 2 infantile cases and review of the differential diagnosis of infantile pulmonary lesions
Tanaka M, Kohashi K, Kushitani K, Yoshida M, Kurihara S, Kawashima M, Ueda Y, Souzaki R, Kinoshita Y, Oda Y, Takeshima Y, Hiyama E, Taguchi T, Tanaka Y
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Alpha-2 macroglobulin I1000 V polymorphism in Chinese sporadic Alzheimer's disease and Parkinson's disease
Tang G, Zhang M, Xie H, Jiang S, Wang Z, Xu L, Hao Y, Lin D, Lan H, Wang Y, Chen L, Ren D
Neurosci Lett 2002 Aug 9;328(2):195-7
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The subunits of alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein, native and transformed alpha2-macroglobulin and interleukin 6 in Alzheimer's disease
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Brain Res 1997 Nov 28;777(1-2):223-7
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Localization of alpha 2-macroglobulin protein and messenger RNA in rat liver fibrosis: evidence for the synthesis of alpha 2-macroglobulin within Schistosoma mansoni egg granulomas
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Citation

This paper should be referenced as such :
Gurbanov R, Samgane G
A2M (alpha-2-macroglobulin);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/A2MID42923ch12p13.html



Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  t(2;12)(p23;p13) A2M/ALK
t(11;12)(p15;p13) A2M/FAR1
t(12;20)(p13;q13) A2M/ARFGEF2


External links

Nomenclature
HGNC (Hugo)A2M   7
Cards
AtlasA2MID42923ch12p13.txt
Entrez_Gene (NCBI)A2M  2  alpha-2-macroglobulin
AliasesA2MD; CPAMD5; FWP007; S863-7
GeneCards (Weizmann)A2M
Ensembl hg19 (Hinxton)ENSG00000175899 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000175899 [Gene_View]  ENSG00000175899 [Sequence]  chr12:9067708-9115919 [Contig_View]  A2M [Vega]
ICGC DataPortalENSG00000175899
TCGA cBioPortalA2M
AceView (NCBI)A2M
Genatlas (Paris)A2M
WikiGenes2
SOURCE (Princeton)A2M
Genetics Home Reference (NIH)A2M
Genomic and cartography
GoldenPath hg38 (UCSC)A2M  -     chr12:9067708-9115919 -  12p13.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)A2M  -     12p13.31   [Description]    (hg19-Feb_2009)
GoldenPathA2M - 12p13.31 [CytoView hg19]  A2M - 12p13.31 [CytoView hg38]
ImmunoBaseENSG00000175899
Mapping of homologs : NCBIA2M [Mapview hg19]  A2M [Mapview hg38]
OMIM103950   104300   
Gene and transcription
Genbank (Entrez)AB209614 AK307832 AK312482 AY591530 BC026246
RefSeq transcript (Entrez)NM_000014 NM_001347423 NM_001347424 NM_001347425
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)A2M
Alternative Splicing GalleryENSG00000175899
Gene ExpressionA2M [ NCBI-GEO ]   A2M [ EBI - ARRAY_EXPRESS ]   A2M [ SEEK ]   A2M [ MEM ]
Gene Expression Viewer (FireBrowse)A2M [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2
GTEX Portal (Tissue expression)A2M
Human Protein AtlasENSG00000175899-A2M [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP01023   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP01023  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP01023
Splice isoforms : SwissVarP01023
PhosPhoSitePlusP01023
Domaine pattern : Prosite (Expaxy)ALPHA_2_MACROGLOBULIN (PS00477)   
Domains : Interpro (EBI)A-macroglobulin_rcpt-bd    A-macroglobulin_rcpt-bd_sf    A2M_N_BRD    A2M_TED    Alpha-macroglobulin_TED    Ig-like_fold    Ig_E-set    Macroglobln_a2    MacrogloblnA2_CS    MG2    MG3    MG4    Terpenoid_cyclase/PrenylTrfase    TonB_box_CS   
Domain families : Pfam (Sanger)A2M (PF00207)    A2M_BRD (PF07703)    A2M_recep (PF07677)    MG2 (PF01835)    MG3 (PF17791)    MG4 (PF17789)    TED_complement (PF07678)   
Domain families : Pfam (NCBI)pfam00207    pfam07703    pfam07677    pfam01835    pfam17791    pfam17789    pfam07678   
Domain families : Smart (EMBL)A2M (SM01360)  A2M_N_2 (SM01359)  A2M_recep (SM01361)  
Conserved Domain (NCBI)A2M
DMDM Disease mutations2
Blocks (Seattle)A2M
PDB (RSDB)1BV8    2P9R    4ACQ   
PDB Europe1BV8    2P9R    4ACQ   
PDB (PDBSum)1BV8    2P9R    4ACQ   
PDB (IMB)1BV8    2P9R    4ACQ   
Structural Biology KnowledgeBase1BV8    2P9R    4ACQ   
SCOP (Structural Classification of Proteins)1BV8    2P9R    4ACQ   
CATH (Classification of proteins structures)1BV8    2P9R    4ACQ   
SuperfamilyP01023
Human Protein Atlas [tissue]ENSG00000175899-A2M [tissue]
Peptide AtlasP01023
HPRD00072
IPIIPI00478003   IPI01010737   IPI00878729   IPI01014689   IPI01015090   IPI01013706   
Protein Interaction databases
DIP (DOE-UCLA)P01023
IntAct (EBI)P01023
FunCoupENSG00000175899
BioGRIDA2M
STRING (EMBL)A2M
ZODIACA2M
Ontologies - Pathways
QuickGOP01023
Ontology : AmiGO"negative regulation of complement activation, lectin pathway  protease binding  protease binding  platelet degranulation  endopeptidase inhibitor activity  serine-type endopeptidase inhibitor activity  signaling receptor binding  protein binding  extracellular region  extracellular region  extracellular space  cytosol  blood coagulation, intrinsic pathway  negative regulation of endopeptidase activity  growth factor binding  enzyme binding  interleukin-8 binding  interleukin-1 binding  extracellular matrix disassembly  platelet alpha granule lumen  tumor necrosis factor binding  calcium-dependent protein binding  stem cell differentiation  regulation of small GTPase mediated signal transduction  collagen-containing extracellular matrix  collagen-containing extracellular matrix  extracellular exosome  blood microparticle"  
Ontology : EGO-EBI"negative regulation of complement activation, lectin pathway  protease binding  protease binding  platelet degranulation  endopeptidase inhibitor activity  serine-type endopeptidase inhibitor activity  signaling receptor binding  protein binding  extracellular region  extracellular region  extracellular space  cytosol  blood coagulation, intrinsic pathway  negative regulation of endopeptidase activity  growth factor binding  enzyme binding  interleukin-8 binding  interleukin-1 binding  extracellular matrix disassembly  platelet alpha granule lumen  tumor necrosis factor binding  calcium-dependent protein binding  stem cell differentiation  regulation of small GTPase mediated signal transduction  collagen-containing extracellular matrix  collagen-containing extracellular matrix  extracellular exosome  blood microparticle"  
Pathways : KEGGComplement and coagulation cascades   
REACTOMEP01023 [protein]
REACTOME PathwaysR-HSA-8963896 [pathway]   
NDEx NetworkA2M
Atlas of Cancer Signalling NetworkA2M
Wikipedia pathwaysA2M
Orthology - Evolution
OrthoDB2
GeneTree (enSembl)ENSG00000175899
Phylogenetic Trees/Animal Genes : TreeFamA2M
HOGENOMP01023
Homologs : HomoloGeneA2M
Homology/Alignments : Family Browser (UCSC)A2M
Gene fusions - Rearrangements
Fusion : MitelmanA2M/ALK [12p13.31/2p23.2]  
Fusion : MitelmanA2M/ARFGEF2 [12p13.31/20q13.13]  [t(12;20)(p13;q13)]  
Fusion : MitelmanA2M/FAR1 [12p13.31/11p15.2]  [t(11;12)(p15;p13)]  
Fusion PortalA2M 12p13.31 ARFGEF2 20q13.13 LUAD
Fusion PortalA2M 12p13.31 FAR1 11p15.2 KIRC
Fusion Cancer (Beijing)A2M [12p13.31]  -  ABR [17p13.3]  [FUSC002083]
Fusion Cancer (Beijing)A2M [12p13.31]  -  C2orf39 [FUSC002085]
Fusion Cancer (Beijing)A2M [12p13.31]  -  DNAJB7 [22q13.2]  [FUSC002091]
Fusion Cancer (Beijing)A2M [12p13.31]  -  KIFC3 [16q21]  [FUSC002049]
Fusion Cancer (Beijing)A2M [12p13.31]  -  NSUN2 [5p15.31]  [FUSC002099]
Fusion Cancer (Beijing)A2M [12p13.31]  -  PLEKHA5 [12p12.3]  [FUSC002100]
Fusion Cancer (Beijing)A2M [12p13.31]  -  PZP [12p13.31]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]  [FUSC001904]
Fusion Cancer (Beijing)A2M [12p13.31]  -  RPS12 [6q23.2]  [FUSC002102]
Fusion Cancer (Beijing)A2M [12p13.31]  -  WIPF2 [17q21.1]  [FUSC002802]
Fusion Cancer (Beijing)ALG8 [11q14.1]  -  A2M [12p13.31]  [FUSC002118]
Fusion Cancer (Beijing)POLR3C [1q21.1]  -  A2M [12p13.31]  [FUSC002183]
Fusion : Fusion_HubA2M--A1BG    A2M--A2M    A2M--ABP1    A2M--ABR    A2M--AFMID    A2M--ALB    A2M--ALDH5A1    A2M--ALK    A2M--ANKRD6    A2M--ARFGEF2    A2M--ATXN3    A2M--BAHD1    A2M--BRD7    A2M--C13ORF40    A2M--C14ORF180   
A2M--C1QTNF6    A2M--C1S    A2M--C2ORF16    A2M--C2ORF39    A2M--C3ORF54    A2M--C8ORF34    A2M--C9ORF114    A2M--CARM1    A2M--CCT5    A2M--CHL1    A2M--CHMP1A    A2M--CLU    A2M--CNP    A2M--COL3A1    A2M--CPAMD8   
A2M--CRP    A2M--CSRNP3    A2M--CSRP1    A2M--CYB561    A2M--DCLK1    A2M--DDB1    A2M--DGAT1    A2M--DNAJA4    A2M--DNAJB7    A2M--EMILIN2    A2M--ENTPD4    A2M--EPAS1    A2M--EPN2    A2M--EXD1    A2M--FAR1   
A2M--FGG    A2M--FXYD5    A2M--GEM    A2M--GMFG    A2M--HDX    A2M--HNRNPD    A2M--HP    A2M--HP1BP3    A2M--INVS    A2M--ITCH    A2M--KALRN    A2M--KIAA1210    A2M--KIAA1430    A2M--KIF5C    A2M--KIFC3   
A2M--KLHDC8B    A2M--LARGE    A2M--LOC285548    A2M--LPIN2    A2M--MAPT    A2M--MB    A2M--MED23    A2M--MIAT    A2M--MST4    A2M--NAA11    A2M--NEB    A2M--NME4    A2M--NOL10    A2M--NSUN2    A2M--OFD1   
A2M--PABPN1    A2M--PIP5K1P1    A2M--PLEKHA5    A2M--PNMA2    A2M--PPFIBP1    A2M--PRC1    A2M--PZP    A2M--RASGEF1C    A2M--REG3G    A2M--RNF216    A2M--RPL5    A2M--RPS12    A2M--SCML4    A2M--SFSWAP    A2M--SFTPA1   
A2M--SFTPC    A2M--SIK1    A2M--SLC23A1    A2M--SLC4A5    A2M--SLC6A6    A2M--SRPK1    A2M--TADA2A    A2M--TFAMP1    A2M--TG    A2M--TGM2    A2M--TK2    A2M--TMED9    A2M--TMTC4    A2M--TRAK2    A2M--TXNDC17   
A2M--UBD    A2M--UTP23    A2M--VIM    A2M--VPS28    A2M--WIPF2    A2M--XRN2    A2M--ZNF75D    A2M--ZNF814    A2ML1--A2M    ABCC2--A2M    AC109583.1--A2M    ACPP--A2M    ALG8--A2M    ALK--A2M    ATP5G2--A2M   
BMP8B--A2M    C12ORF33--A2M    C1ORF151--A2M    C1ORF198--A2M    CD1B--A2M    CDH23--A2M    EIF3B--A2M    FRAT1--A2M    IGKC--A2M    IL16--A2M    KLRG1--A2M    KRR1--A2M    LARS--A2M    LMO4--A2M    LOC100128682--A2M   
MARK1--A2M    MERTK--A2M    NBPF1--A2M    PCGF5--A2M    PIP5K1A--A2M    PKD1--A2M    POLR3C--A2M    SLC25A45--A2M    SUV39H2--A2M    TAX1BP3--A2M    TEX26--A2M    TUBB4B--A2M    UQCC2--A2M    VAMP1--A2M    WDR77--A2M   
ZC3H15--A2M    ZNF605--A2M   
Fusion : QuiverA2M
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerA2M [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)A2M
dbVarA2M
ClinVarA2M
1000_GenomesA2M 
Exome Variant ServerA2M
ExAC (Exome Aggregation Consortium)ENSG00000175899
GNOMAD BrowserENSG00000175899
Varsome BrowserA2M
Genetic variants : HAPMAP2
Genomic Variants (DGV)A2M [DGVbeta]
DECIPHERA2M [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisA2M 
Mutations
ICGC Data PortalA2M 
TCGA Data PortalA2M 
Broad Tumor PortalA2M
OASIS PortalA2M [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICA2M  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DA2M
Mutations and Diseases : HGMDA2M
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch A2M
DgiDB (Drug Gene Interaction Database)A2M
DoCM (Curated mutations)A2M (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)A2M (select a term)
intoGenA2M
NCG5 (London)A2M
Cancer3DA2M(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM103950    104300   
Orphanet
DisGeNETA2M
MedgenA2M
Genetic Testing Registry A2M
NextProtP01023 [Medical]
TSGene2
GENETestsA2M
Target ValidationA2M
Huge Navigator A2M [HugePedia]
snp3D : Map Gene to Disease2
BioCentury BCIQA2M
ClinGenA2M
Clinical trials, drugs, therapy
Protein Interactions : CTD2
Pharm GKB GenePA24357
Clinical trialA2M
Miscellaneous
canSAR (ICR)A2M (select the gene name)
HarmonizomeA2M
DataMed IndexA2M
Probes
Litterature
PubMed262 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineA2M
EVEXA2M
GoPubMedA2M
iHOPA2M
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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