{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Collagen type IV α2 (COL4A2) is a critical structural component of basement membranes that partners with collagen IV α1 (COL4A1) to form heterotrimers essential for extracellular matrix integrity, vascular stability, and cell–matrix interactions. Several studies have shown that proper secretion and assembly of COL4A2 is indispensable for maintaining the normal function of cerebral and systemic vasculature. Mutations in COL4A2—often involving glycine substitutions in its conserved triple‐helical domain—disrupt folding and secretion, leading to intracellular accumulation, endoplasmic reticulum stress, and ultimately contributing to small vessel disease, intracerebral hemorrhage, and porencephaly."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, regulatory mechanisms modulating COL4A2 expression are significant for tissue homeostasis. For example, miR‐29a directly targets the 3′ untranslated regions of both COL4A1 and COL4A2, acting as a repressor to fine‐tune collagen IV abundance; reductions in miR‐29a under high‐glucose conditions may therefore predispose to excess collagen deposition in diabetic nephropathy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, comparative mutagenesis studies in mice have demonstrated that heterozygous missense mutations in Col4a2 can result in defects across several organs—including eyes, brain, kidneys, and vasculature—highlighting its role in multi‐system development and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Population‐based genetic studies further support the importance of COL4A2 in vascular health by linking common intronic polymorphisms in COL4A2 to an increased risk of deep intracerebral hemorrhage and symptomatic small vessel disease, thereby emphasizing its role in cerebral vessel integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Detailed analyses of mutation allelic heterogeneity have confirmed that the exact position of glycine substitutions in the collagenous domain influences the clinical severity of cerebrovascular and extracerebral manifestations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Altered COL4A2 expression is also implicated in pathological tissue remodeling. For instance, studies of uterine leiomyomas have revealed aberrant expression of collagen-related genes including COL4A2, suggesting a role in modifying the tumor extracellular matrix microenvironment"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while reduced expression of COL4A2 in pulmonary arterial endothelial cells correlates with impaired cell adhesion, migration, and tube formation, linking its downregulation to endothelial dysfunction in pulmonary arterial hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, these findings underscore that COL4A2 is pivotal for basement membrane structure and function. Perturbations in its expression or mutations that affect its stability and secretion not only compromise tissue integrity but also predispose individuals to a spectrum of vascular and organ-specific pathologies.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marion Jeanne, Cassandre Labelle-Dumais, Jeff Jorgensen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2011.11.022"}], "href": "https://doi.org/10.1016/j.ajhg.2011.11.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22209247"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22209247"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elly Verbeek, Marije E C Meuwissen, Frans W Verheijen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "COL4A2 mutation associated with familial porencephaly and small-vessel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2012.20"}], "href": "https://doi.org/10.1038/ejhg.2012.20"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22333902"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22333902"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marion Jeanne, Jeff Jorgensen, Douglas B Gould "}, {"type": "b", "children": [{"type": "t", "text": "Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.114.013395"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.114.013395"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25753534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25753534"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bin Du, Li-Ming Ma, Mian-Bo Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2009.12.053"}], "href": "https://doi.org/10.1016/j.febslet.2009.12.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20067797"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20067797"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jack Favor, Christian Johannes Gloeckner, Dirk Janik, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Type IV procollagen missense mutations associated with defects of the eye, vascular stability, the brain, kidney function and embryonic or postnatal viability in the mouse, Mus musculus: an extension of the Col4a1 allelic series and the identification of the first two Col4a2 mutant alleles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genetics (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1534/genetics.106.064733"}], "href": "https://doi.org/10.1534/genetics.106.064733"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17179069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17179069"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kristiina Rannikmäe, Gail Davies, Pippa A Thomson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/WNL.0000000000001309"}], "href": "https://doi.org/10.1212/WNL.0000000000001309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25653287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25653287"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Marion Jeanne, Douglas B Gould "}, {"type": "b", "children": [{"type": "t", "text": "Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2016.10.003"}], "href": "https://doi.org/10.1016/j.matbio.2016.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27794444"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27794444"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ryo Maekawa, Shun Sato, Yoshiaki Yamagata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0066632"}], "href": "https://doi.org/10.1371/journal.pone.0066632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23818951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23818951"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Christopher J Rhodes, Hogune Im, Aiqin Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Crit Care Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1164/rccm.201408-1528OC"}], "href": "https://doi.org/10.1164/rccm.201408-1528OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26030479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26030479"}]}]}]}