A2ML1 is a secreted broad-spectrum protease inhibitor of the alpha-2-macroglobulin family expressed in stratified epithelia and other tissues, where it was first identified as the p170 autoantigen recognized by paraneoplastic pemphigus autoantibodies PMID:20805888. Loss-of-function variants in A2ML1 confer susceptibility to otitis media: rare and damaging variants cosegregate with disease in human pedigrees and otitis-prone children PMID:26121085, variant carriers show reduced A2ML1 expression PMID:31009165, and A2ml1-knockout mice develop spontaneous middle ear disease with tympanic membrane perforation and effusion accompanied by upregulation of desmoplakin (Dsp), implicating dysregulated keratinocyte/epithelial integrity as the disease mechanism PMID:38759260. In pancreatic cancer, A2ML1 is overexpressed and promotes progression and epithelial-mesenchymal transition by downregulating LZTR1 and activating the KRAS/MAPK pathway PMID:40615919. Heterozygous germline A2ML1 variants were associated with a Noonan-syndrome-like phenotype in a zebrafish model PMID:24939586, but a systematic segregation analysis across RASopathy families found these variants inherited from unaffected parents alongside alternative disease-causing aberrations, not supporting a causal role in Noonan syndrome PMID:33082526.
| Year | Confidence | Finding | PMIDs | Journal |
|---|---|---|---|---|
| 2010 | High | A2ML1 (alpha-2-macroglobulin-like-1) was identified as the p170 antigen recognized by autoantibodies in paraneoplastic pemphigus (PNP). Using immunoprecipitation followed by mass spectrometry, A2ML1 was shown to be a broad-range protease inhibitor expressed in stratified epithelia and other tissues damaged in PNP. Ten PNP sera recognized A2ML1, while none of the control sera from patients with bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, or normal subjects did. | PMID:20805888 | PloS one |
| 2014 | Medium | Heterozygous germline mutations in A2ML1 (p.Arg802His, p.Arg802Leu, p.Arg592Leu) cause a disorder clinically related to Noonan syndrome. Functional characterization in zebrafish showed NS-like developmental defects including broad head, blunted face, and cardiac malformations. Using the crystal structure of the highly homologous A2M, p.Arg802 was identified as an intramolecular interaction residue; mutation of its interaction partner p.Glu906 induced similar developmental defects in zebrafish, supporting a structural mechanism for pathogenicity. | PMID:24939586 | European journal of human genetics : EJHG |
| 2015 | Medium | Rare variants in A2ML1, including a duplication variant, cosegregate with otitis media susceptibility in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and are found in otitis-prone US children but absent in non-otitis-prone children and >62,000 controls. Seven additional A2ML1 variants were identified in otitis-prone children, supporting a role for A2ML1 in otitis media pathophysiology. | PMID:26121085 | Nature genetics |
| 2019 | Low | Sixteen novel damaging A2ML1 variants were identified in otitis media patients and shown to be rare or low-frequency in population-matched controls. Sequencing of salivary RNA showed lower A2ML1 expression in A2ML1 variant carriers. Differentially expressed genes correlated with A2ML1 expression levels included RND3 (upregulated in both A2ML1 variant carriers and high-A2ML1 expressors), supporting a role for A2ML1 in keratinocyte differentiation within the middle ear, potentially through ROCK signaling. | PMID:31009165 | Human mutation |
| 2020 | Low | A2ML1 protein accumulates in the amnion during pregnancy in humans, while in the common marmoset (where PZP is absent), A2ML1 shows the most prominent increase in expression during the second trimester and is detected in placenta. Both human PZP and marmoset A2ML1 belong to the A2M family of protease inhibitors with highly conserved structures; the protease-reacting bait regions have lower inter-species homology (56.8–60.7%), and a cleavage site for proinflammatory proline-endopeptidase is preserved in both proteins. | PMID:32198464 | Scientific reports |
| 2024 | Medium | A2ml1-knockout (CRISPR-induced) mice showed a significantly increased incidence of spontaneous otitis media (odds ratio = 11; p = 0.02) with tympanic membrane perforations, middle ear effusion, and inflammatory cells. Dsp (desmoplakin) was upregulated in middle ear tissues of homozygous knockout mice, suggesting dysregulation of keratinocyte/epithelial integrity as a disease mechanism for A2ml1-related otitis media. | PMID:38759260 | International journal of pediatric otorhinolaryngology |
| 2025 | Medium | A2ML1 expression was found significantly elevated in pancreatic cancer tissues compared to normal tissue. Functional experiments showed that A2ML1 promotes pancreatic cancer progression through downregulation of LZTR1 expression and subsequent activation of the KRAS/MAPK pathway, ultimately driving epithelial-mesenchymal transition (EMT). | PMID:40615919 | Journal of translational medicine |
| 2020 | Medium | The clinical significance of A2ML1 variants in Noonan syndrome was called into question: in 15 individuals found to carry rare A2ML1 variants (including previously proposed causative variants) during RASopathy screening, inherited variants came from unaffected parents, and 7 index patients carried an alternative disease-causing genetic aberration. This negative replication study does not support a causal role for A2ML1 in Noonan syndrome. | PMID:33082526 | European journal of human genetics : EJHG |