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A2ML1 alpha-2-macroglobulin like 1 [ Homo sapiens (human) ]

Gene ID: 144568, updated on 3-Apr-2024

Summary

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Official Symbol
A2ML1provided by HGNC
Official Full Name
alpha-2-macroglobulin like 1provided by HGNC
Primary source
HGNC:HGNC:23336
See related
Ensembl:ENSG00000166535 MIM:610627; AllianceGenome:HGNC:23336
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
OMS; p170; CPAMD9
Summary
This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
Expression
Restricted expression toward esophagus (RPKM 190.0) See more
Orthologs
all
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Genomic context

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See A2ML1 in Genome Data Viewer
Location:
12p13.31
Exon count:
40
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 12 NC_000012.12 (8822621..8887459)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 12 NC_060936.1 (8805910..8869474)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 12 NC_000012.11 (8975217..9029383)

Chromosome 12 - NC_000012.12Genomic Context describing neighboring genes Neighboring gene ribosomal modification protein rimK like family member B Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8924703-8925204 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8925205-8925704 Neighboring gene ribosomal protein SA pseudogene 51 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8940201-8940740 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8940741-8941280 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8941281-8941820 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr12:8941899-8942576 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr12:8942577-8943254 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8947958-8948568 Neighboring gene A2ML1 antisense RNA 1 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8957581-8958288 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8958995-8959702 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8962654-8963394 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8963395-8964136 Neighboring gene long intergenic non-protein coding RNA 2972 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8967023-8967549 Neighboring gene Sharpr-MPRA regulatory region 8322 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8980966-8981708 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8984681-8985424 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9057572-9058228 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:9060851-9061506 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr12:9064238-9064790 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4218 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4219 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4220 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9101505-9102410 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9102411-9103315 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr12:9108425-9109624 Neighboring gene polyhomeotic homolog 1 Neighboring gene mannose-6-phosphate receptor, cation dependent Neighboring gene killer cell lectin like receptor G1 Neighboring gene VDAC2 pseudogene 2

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family. Nielsen NS, et al. Nat Commun, 2022 May 31. PMID 35641520, Free PMC Article
  2. The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered. Brinkmann J, et al. Eur J Hum Genet, 2021 Mar. PMID 33082526, Free PMC Article
  3. A2ML1 and otitis media: novel variants, differential expression, and relevant pathways. Larson ED, et al. Hum Mutat, 2019 Aug. PMID 31009165, Free PMC Article
  4. Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene. Santos-Cortez RL, et al. Infect Dis Poverty, 2016 Nov 1. PMID 27799062, Free PMC Article
  5. Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population. Santos-Cortez RL, et al. Otolaryngol Head Neck Surg, 2016 Nov. PMID 27484237, Free PMC Article

See all (47) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.
    Title: A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.
  2. Audiologic Measures in an Indigenous Community with A2ML1- and FUT2-Related Otitis Media.
    Title: Audiologic Measures in an Indigenous Community with A2ML1- and FUT2-Related Otitis Media.
  3. Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
    Title: Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
  4. The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.
    Title: The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.
  5. Study identified 16 novel A2ML1 variants in otitis media patients, two of which are pathogenic further providing evidence to support a role for A2ML1 in middle ear mucosal pathology. Sequencing of patients salivary RNA samples demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants.
    Title: A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.
  6. The functional assessment supported the pathogenicity of the RAF1 and RIT1 variants of unknown significance (VUSs), while the significance of two VUSs in A2ML1 remained unclear.
    Title: Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies.
  7. Brain gene expression of PADI2, ZNF385A, PSD2, and A2ML1 and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.
    Title: Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline.
  8. The indigenous Filipino population has a ~50% prevalence of otitis media. A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.
    Title: Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.
  9. A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome.
    Title: Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.
  10. Studies support a role for alpha-2-macroglobulin-like 1 protein (A2ML1) in the pathophysiology of otitis media.
    Title: Rare A2ML1 variants confer susceptibility to otitis media.
Submit: New GeneRIF Correction See all GeneRIFs (15)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Otitis media, susceptibility to
MedGen: C1833692 OMIM: 166760 GeneReviews: Not available
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EBI GWAS Catalog

Description
Discovery and refinement of loci associated with lipid levels.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Clone Names

  • FLJ16045, FLJ25179, FLJ39129, FLJ41597, FLJ41598, FLJ41607, DKFZp686C1729, DKFZp686D2011, DKFZp686G1812, DKFZp686L1821, DKFZp686O1010

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables peptidase inhibitor activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables serine-type endopeptidase inhibitor activity IEA
Inferred from Electronic Annotation
more info
  
Process Evidence Code Pubs
involved_in regulation of endopeptidase activity IDA
Inferred from Direct Assay
more info
 PubMed 
Component Evidence Code Pubs
located_in extracellular exosome HDA PubMed 
located_in extracellular space IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
alpha-2-macroglobulin-like protein 1
Names
C3 and PZP-like, alpha-2-macroglobulin domain containing 9

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_042857.2 RefSeqGene

    Range
    5002..59168
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001282424.3 → NP_001269353.2  alpha-2-macroglobulin-like protein 1 isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) represents use of an alternate promoter, and thus differs in the 5' UTR and 5' coding region, compared to variant 1. These differences cause translation initiation at an alternate AUG, and the resulting isoform (2) has a distinct and shorter N-terminus compared to isoform 1.
    Source sequence(s)
    AC006513, AC006581
    Consensus CDS
    CCDS73439.1
    UniProtKB/TrEMBL
    H0YGG5
    Related
    ENSP00000438292.1, ENST00000539547.5
    Conserved Domains (4) summary
    cd02897
    Location:465 → 760
    A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
    pfam00207
    Location:245 → 335
    A2M; Alpha-2-macroglobulin family
    pfam07677
    Location:871 → 958
    A2M_recep; A-macroglobulin receptor
    pfam07703
    Location:1 → 110
    A2M_N_2; Alpha-2-macroglobulin family N-terminal region

  2. NM_144670.6 → NP_653271.3  alpha-2-macroglobulin-like protein 1 isoform 1 precursor

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
    Source sequence(s)
    AC006513, AC006581
    Consensus CDS
    CCDS8596.2
    UniProtKB/Swiss-Prot
    A8K2U0, B5MDD1, B7Z7V4, D3DUV3, F5H2Z2, Q2M224, Q6ZW52, Q6ZW53, Q8N1M4, Q96LQ8
    UniProtKB/TrEMBL
    B3KVV6
    Related
    ENSP00000299698.7, ENST00000299698.12
    Conserved Domains (5) summary
    cd02897
    Location:956 → 1251
    A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
    pfam00207
    Location:736 → 826
    A2M; Alpha-2-macroglobulin family
    pfam01835
    Location:122 → 211
    A2M_N; MG2 domain
    pfam07677
    Location:1362 → 1449
    A2M_recep; A-macroglobulin receptor
    pfam07703
    Location:459 → 601
    A2M_N_2; Alpha-2-macroglobulin family N-terminal region

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000012.12 Reference GRCh38.p14 Primary Assembly

    Range
    8822621..8887459
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_011520566.3 → XP_011518868.1  alpha-2-macroglobulin-like protein 1 isoform X1

    See identical proteins and their annotated locations for XP_011518868.1

    UniProtKB/TrEMBL
    B3KVV6
    Conserved Domains (7) summary
    COG2373
    Location:123 → 1055
    YfaS; Uncharacterized conserved protein YfaS, alpha-2-macroglobulin family [General function prediction only]
    cd02897
    Location:969 → 1264
    A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
    pfam00207
    Location:749 → 839
    A2M; Alpha-2-macroglobulin family
    pfam01835
    Location:122 → 211
    A2M_N; MG2 domain
    pfam07677
    Location:1375 → 1462
    A2M_recep; A-macroglobulin receptor
    pfam07678
    Location:1021 → 1266
    A2M_comp; A-macroglobulin complement component
    pfam07703
    Location:455 → 613
    A2M_N_2; Alpha-2-macroglobulin family N-terminal region

  2. XM_047428387.1 → XP_047284343.1  alpha-2-macroglobulin-like protein 1 isoform X4

  3. XM_011520567.3 → XP_011518869.1  alpha-2-macroglobulin-like protein 1 isoform X1

    See identical proteins and their annotated locations for XP_011518869.1

    UniProtKB/TrEMBL
    B3KVV6
    Conserved Domains (7) summary
    COG2373
    Location:123 → 1055
    YfaS; Uncharacterized conserved protein YfaS, alpha-2-macroglobulin family [General function prediction only]
    cd02897
    Location:969 → 1264
    A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
    pfam00207
    Location:749 → 839
    A2M; Alpha-2-macroglobulin family
    pfam01835
    Location:122 → 211
    A2M_N; MG2 domain
    pfam07677
    Location:1375 → 1462
    A2M_recep; A-macroglobulin receptor
    pfam07678
    Location:1021 → 1266
    A2M_comp; A-macroglobulin complement component
    pfam07703
    Location:455 → 613
    A2M_N_2; Alpha-2-macroglobulin family N-terminal region

  4. XM_017018869.2 → XP_016874358.1  alpha-2-macroglobulin-like protein 1 isoform X2

    UniProtKB/TrEMBL
    B3KVV6

  5. XM_017018870.2 → XP_016874359.1  alpha-2-macroglobulin-like protein 1 isoform X3

    UniProtKB/Swiss-Prot
    A8K2U0, B5MDD1, B7Z7V4, D3DUV3, F5H2Z2, Q2M224, Q6ZW52, Q6ZW53, Q8N1M4, Q96LQ8
    UniProtKB/TrEMBL
    B3KVV6
    Conserved Domains (5) summary
    cd02897
    Location:956 → 1251
    A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
    pfam00207
    Location:736 → 826
    A2M; Alpha-2-macroglobulin family
    pfam01835
    Location:122 → 211
    A2M_N; MG2 domain
    pfam07677
    Location:1362 → 1449
    A2M_recep; A-macroglobulin receptor
    pfam07703
    Location:459 → 601
    A2M_N_2; Alpha-2-macroglobulin family N-terminal region

RNA

  1. XR_931275.2 RNA Sequence

  2. XR_001748594.2 RNA Sequence

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060936.1 Alternate T2T-CHM13v2.0

    Range
    8805910..8869474
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054371194.1 → XP_054227169.1  alpha-2-macroglobulin-like protein 1 isoform X1

  2. XM_054371198.1 → XP_054227173.1  alpha-2-macroglobulin-like protein 1 isoform X4

  3. XM_054371195.1 → XP_054227170.1  alpha-2-macroglobulin-like protein 1 isoform X1

  4. XM_054371196.1 → XP_054227171.1  alpha-2-macroglobulin-like protein 1 isoform X2

  5. XM_054371197.1 → XP_054227172.1  alpha-2-macroglobulin-like protein 1 isoform X3

RNA

  1. XR_008488540.1 RNA Sequence

  2. XR_008488539.1 RNA Sequence

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
A8K2U0.3 GenPept UniProtKB/Swiss-Prot:A8K2U0

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