{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWithin the leucine‐rich repeat protein family that orchestrates immune regulation, NRROS (Negative Regulator of Reactive Oxygen Species) plays a pivotal role in linking latent transforming growth factor‐β1 (TGF‑β1) activation to the control of inflammatory signaling. Related family members such as LRRC33 have been shown to desensitize Toll‑like receptor (TLR) signaling by curbing NF‑κB and AP‑1 activation and by modulating cytokine production, in part through controlled membrane presentation of latent TGF‑β1 via integrin‐dependent mechanisms (1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast to its LRR counterparts, NRROS uniquely associates with latent TGF‑β1—anchoring it to the cell surface in macrophages and microglia—and thereby facilitates its subsequent integrin‐dependent activation. Disruption of this anchoring function due to biallelic mutations in NRROS impairs proper TGF‑β1 presentation, leading to a cascade of downstream defects in inflammatory modulation and neural homeostasis. Clinically, affected individuals manifest severe neurodegenerative disease characterized by refractory epilepsy, developmental regression, delayed myelination, and intracranial calcifications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdding to its critical role in neuroimmune regulation, genetic variation in the NRROS locus has been linked to immune-mediated conditions. Specifically, a single nucleotide polymorphism within the FBXO45‑NRROS gene region has been significantly associated with vitiligo susceptibility in the Chinese Han population, suggesting that altered NRROS function may predispose to autoimmune dysregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wenjiang Ma, Yan Qin, Bjoern Chapuy, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Epigenetically modulated LRRC33 acts as a negative physiological regulator for multiple Toll-like receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0813457"}], "href": "https://doi.org/10.1189/jlb.0813457"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24550525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24550525"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Zelin Duan, Xuezhen Lin, Lixia Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Specificity of TGF-β1 signal designated by LRRC33 and integrin α"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "V"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": "β"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "8"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": "."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-022-32655-9"}], "href": "https://doi.org/10.1038/s41467-022-32655-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36008481"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36008481"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiaomin Dong, Natalie B Tan, Katherine B Howell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2020.02.014"}], "href": "https://doi.org/10.1016/j.ajhg.2020.02.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32197075"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32197075"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xianfa Tang, Fang Fang, Jingjing Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association Study Reveals One Susceptibility Locus with Vitiligo in the Chinese Han Population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Test Mol Biomarkers (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/gtmb.2019.0129"}], "href": "https://doi.org/10.1089/gtmb.2019.0129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31644309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31644309"}]}]}]}