{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Neuronal leucine‐rich repeat protein 3 (LRRN3) is a member of a conserved family of transmembrane proteins that contain extracellular leucine‐rich repeats and has been implicated in both neural development and cellular signaling. Initial cloning and characterization studies demonstrated that LRRN3 is predominantly expressed in the developing brain, with expression detected in neural tissues such as ganglia, motor neurons, and the embryonic myotome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Complementary expression studies in the central nervous system further underscored its spatially restricted pattern relative to other neuronal leucine‐rich repeat proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the molecular level, LRRN3 expression is sensitive to mitogenic cues; in fibroblast and neural models, its transcription is upregulated via the Ras–MAPK pathway, and the protein itself appears to facilitate epidermal growth factor internalization, thereby potentiating MAPK signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In neuroblastoma—a tumor derived from neural crest cells—a higher expression of LRRN3 is correlated with markers of differentiation and a favorable clinical outcome, while its proteolytic processing can generate an intracellular domain that suppresses cell proliferation and supports all‐trans retinoic acid–mediated differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " A parallel association has also been observed in autism spectrum disorders, where variations in LRRN3 are linked to susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in neural development, altered LRRN3 expression has emerged as a robust peripheral biomarker in diverse disease settings. Multiple transcriptomic studies have consistently shown that blood levels of LRRN3 are increased in response to cigarette smoking, serving as a reliable indicator of smoking exposure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": " In the cardiovascular context, LRRN3 is one of a small set of genes that remains consistently downregulated in peripheral blood following acute myocardial infarction in patients who subsequently develop heart failure, suggesting a potential role in inflammatory or stress responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In oncology, differential expression of LRRN3 has been identified in uveal melanoma and pheochromocytoma, where its expression contributes to predictive signatures for patient outcome, further emphasizing its potential utility as a prognostic marker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent functional studies in postnatal animal models have also provided direct evidence for LRRN3’s involvement in proper neural circuit formation. In the developing cerebellum, interference with LRRN3 function via antibody injection resulted in reduced expression of the synaptic marker VGluT1, diminished synapse formation within the molecular layer, and impaired balance ability—indicating that LRRN3 is critical for normal cerebellar development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, transcriptomic analyses in the context of statin treatment have shown that LRRN3 expression correlates with cholesterol levels and may serve as a novel marker to predict drug response, highlighting its emerging relevance in metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "H Taniguchi, M Tohyama, T Takagi "}, {"type": "b", "children": [{"type": "t", "text": "Cloning and expression of a novel gene for a protein with leucine-rich repeats in the developing mouse nervous system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Res Mol Brain Res (1996)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/0169-328x(95)00243-l"}], "href": "https://doi.org/10.1016/0169-328x(95"}, {"type": "t", "text": "00243-l) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9011764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9011764"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Bryan P Haines, Rajeev Gupta, C Michael Jones, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The NLRR gene family and mouse development: Modified differential display PCR identifies NLRR-1 as a gene expressed in early somitic myoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2005.01.030"}], "href": "https://doi.org/10.1016/j.ydbio.2005.01.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15893969"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15893969"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jun Aruga "}, {"type": "b", "children": [{"type": "t", "text": "Slitrk6 expression profile in the mouse embryo and its relationship to that of Nlrr3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene Expr Patterns (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1567-133x(03)00141-8"}], "href": "https://doi.org/10.1016/s1567-133x(03"}, {"type": "t", "text": "00141-8) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14643680"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14643680"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "K Fukamachi, Y Matsuoka, C Kitanaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rat neuronal leucine-rich repeat protein-3: cloning and regulation of the gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/bbrc.2001.5579"}], "href": "https://doi.org/10.1006/bbrc.2001.5579"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11549284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11549284"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Katsumi Fukamachi, Yoichiro Matsuoka, Hiroshi Ohno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neuronal leucine-rich repeat protein-3 amplifies MAPK activation by epidermal growth factor through a carboxyl-terminal region containing endocytosis motifs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C200502200"}], "href": "https://doi.org/10.1074/jbc.C200502200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12297494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12297494"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shiho Hamano, Miki Ohira, Eriko Isogai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of novel human neuronal leucine-rich repeat (hNLRR) family genes and inverse association of expression of Nbla10449/hNLRR-1 and Nbla10677/hNLRR-3 with the prognosis of primary neuroblastomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2004)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15138588"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15138588"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jesmin Akter, Atsushi Takatori, Md Sazzadul Islam, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2014.09.065"}], "href": "https://doi.org/10.1016/j.bbrc.2014.09.065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25256744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25256744"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Inês Sousa, Taane G Clark, Richard Holt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Autism (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/2040-2392-1-7"}], "href": "https://doi.org/10.1186/2040-2392-1-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20678249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20678249"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Margaret M Parker, Robert P Chase, Andrew Lamb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA sequencing identifies novel non-coding RNA and exon-specific effects associated with cigarette smoking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genomics (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12920-017-0295-9"}], "href": "https://doi.org/10.1186/s12920-017-0295-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28985737"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28985737"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Florian Martin, Marja Talikka, Nikolai V Ivanov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Meta-Analysis of the Performance of a Blood-Based Exposure Response Gene Signature Across Clinical Studies on the Tobacco Heating System 2.2 (THS 2.2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Pharmacol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fphar.2019.00198"}], "href": "https://doi.org/10.3389/fphar.2019.00198"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30971916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30971916"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Carine Poussin, Vincenzo Belcastro, Florian Martin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crowd-Sourced Verification of Computational Methods and Data in Systems Toxicology: A Case Study with a Heat-Not-Burn Candidate Modified Risk Tobacco Product."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chem Res Toxicol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.chemrestox.6b00345"}], "href": "https://doi.org/10.1021/acs.chemrestox.6b00345"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28085253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28085253"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Congyi Yu, Wenjun Zhou "}, {"type": "b", "children": [{"type": "t", "text": "Peripheral neutrophils and naive CD4 T cells predict the development of heart failure following acute myocardial infarction: A bioinformatic study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Rev Port Cardiol (Engl Ed) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.repce.2021.11.002"}], "href": "https://doi.org/10.1016/j.repce.2021.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34857156"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34857156"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Chufeng Gu, Xin Gu, Yujie Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Cell Dev Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fcell.2021.710558"}], "href": "https://doi.org/10.3389/fcell.2021.710558"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34552928"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34552928"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Insoo Suh, Daniel Shibru, Graeme Eisenhofer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Candidate genes associated with malignant pheochromocytomas by genome-wide expression profiling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/SLA.0b013e3181b248bb"}], "href": "https://doi.org/10.1097/SLA.0b013e3181b248bb"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19661783"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19661783"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jing Yang, Fang Li, Li Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Role of LRRN3 in the cerebellum postnatal development in rats]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhong Nan Da Xue Xue Bao Yi Xue Ban (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3969/j.issn.1672-7347.2011.05.009"}], "href": "https://doi.org/10.3969/j.issn.1672-7347.2011.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21685698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21685698"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hong-Hee Won, Suk Ran Kim, Oh Young Bang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differentially expressed genes in human peripheral blood as potential markers for statin response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Med (Berl) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00109-011-0818-3"}], "href": "https://doi.org/10.1007/s00109-011-0818-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21947165"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21947165"}]}]}]}