{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAMACO, the protein encoded by VWA2, is a secreted extracellular matrix component characterized by an architecture featuring an N‐terminal von Willebrand factor A (VWA) domain followed by additional tandem VWA and epidermal growth factor–like domains. Its gene, with a conserved exon–intron organization, is expressed in various tissues including cartilage, skin, lung, and kidney where it is deposited in selective basement membranes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have revealed that specific haplotypes within the VWA2 coding region are associated with a protective effect against type 1 diabetes, suggesting that natural variation in AMACO may modulate predisposition to autoimmune conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical analyses have further shown that AMACO undergoes unusual posttranslational glycosylation, with overlapping consensus sequences accommodating both elongated O‐glucosylated and O‐fucosylated glycan chains on its epidermal growth factor–like domain. Despite these modifications, secretion is not markedly altered, implying that these sugar modifications may serve a yet‐undefined role in fine tuning the protein’s interactions within the extracellular matrix."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn disease contexts, dysregulation of VWA2 expression appears to contribute to pathogenesis. Transcriptional up‐regulation of VWA2 in colorectal carcinomas—with hypomethylation of regions downstream of its transcriptional start site and enrichment of active histone marks—suggests that AMACO is part of a broader oncogenic program possibly mediated by c‑Myc. Furthermore, rare homozygous or compound heterozygous missense mutations in VWA2 have been identified in patients with Alzheimer’s disease, implicating defective AMACO in the risk of neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gerhard Sengle, Birgit Kobbe, Matthias Morgelin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of AMACO, a new member of the von Willebrand factor A-like domain protein superfamily with a regulated expression in the kidney."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M307794200"}], "href": "https://doi.org/10.1074/jbc.M307794200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14506275"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14506275"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elise Eller, Pnina Vardi, Mark J Daly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IDDM17: polymorphisms in the AMACO gene are associated with dominant protection against type 1A diabetes in a Bedouin Arab family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann N Y Acad Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1196/annals.1337.024"}], "href": "https://doi.org/10.1196/annals.1337.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15699509"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15699509"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jan M Gebauer, Stefan Müller, Franz-Georg Hanisch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "O-glucosylation and O-fucosylation occur together in close proximity on the first epidermal growth factor repeat of AMACO (VWA2 protein)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704820200"}], "href": "https://doi.org/10.1074/jbc.M704820200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18434322"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18434322"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Beatriz González, Ferran Fece de la Cruz, Johanna Kristina Samuelsson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic and transcriptional dysregulation of VWA2 associated with a MYC-driven oncogenic program in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-018-29378-7"}], "href": "https://doi.org/10.1038/s41598-018-29378-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30038405"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30038405"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Julie Hoogmartens, Elisabeth Hens, Sebastiaan Engelborghs, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2020.09.009"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2020.09.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33023779"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33023779"}]}]}]}