{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSORCS3, a member of the VPS10 domain receptor family, has emerged as a critical player in neurodevelopment and the pathogenesis of several brain-related disorders. Genetic studies have implicated SORCS3 in attention-deficit hyperactivity disorder (ADHD), with both common and rare variants linked to altered neurodevelopmental trajectories."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, independent genome‐wide association analyses have associated increased expression of SORCS3 with favorable outcomes in neuropsychiatric and cognitive traits, including those relevant to mood, emotion, and overall synaptic integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Emerging data further suggest that sex‐specific genetic risk factors as well as factors shared with other conditions such as dementia and multiple sclerosis may also involve SORCS3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, SORCS3 is synthesized as a proprotein that undergoes proteolytic processing in distal Golgi compartments to yield a mature receptor predominantly localized at the plasma membrane. Experimental studies in transfected cells have demonstrated that its precursor form is competent for ligand binding and that receptor internalization occurs slowly, suggesting a unique trafficking pattern compared to its homologs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Biochemical and electron microscopy investigations further revealed that the extracellular domain of SORCS3 exists in both monomeric and stable dimeric forms — a process regulated by post-translational glycosylation. High-resolution cryo-EM studies have identified at least three distinct conformations, with specific conserved residues likely controlling its dimerization and ligand interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctionally, SORCS3 operates as a sorting receptor that influences intracellular trafficking and signal transduction. In the central nervous system, aberrations in SORCS3 function have been linked to severe clinical phenotypes — including a case of early-onset neurological deterioration associated with a homozygous missense variant — underscoring its importance in neural proliferation and viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Additionally, in the context of glioblastoma, reduced expression of SORCS3 has been correlated with increased tumor cell invasion and proliferation, with the receptor shown to modulate neurotrophin receptor (p75NTR) internalization and lysosomal degradation, thereby attenuating oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ditte Demontis, G Bragi Walters, Georgios Athanasiadis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41588-022-01285-8"}], "href": "https://doi.org/10.1038/s41588-022-01285-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36702997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36702997"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Muhammad Kamran, Aodán Laighneach, Farhana Bibi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Independent Associated SNPs at SORCS3 and Its Protein Interactors for Multiple Brain-Related Disorders and Traits."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes (Basel) (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/genes14020482"}], "href": "https://doi.org/10.3390/genes14020482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36833409"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36833409"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Elizabeth E Blue, Timothy A Thornton, Charles Kooperberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alzheimers Dement (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/alz.12181"}], "href": "https://doi.org/10.1002/alz.12181"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32966694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32966694"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "S Binzer, E Stenager, M Binzer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mult Scler (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1352458515602338"}], "href": "https://doi.org/10.1177/1352458515602338"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26362888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26362888"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "U B Westergaard, K Kirkegaard, E S Sørensen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SorCS3 does not require propeptide cleavage to bind nerve growth factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2004.12.088"}], "href": "https://doi.org/10.1016/j.febslet.2004.12.088"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15710408"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15710408"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Dovile Januliene, Arulmani Manavalan, Peter Lund Ovesen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hidden Twins: SorCS Neuroreceptors Form Stable Dimers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2017.08.006"}], "href": "https://doi.org/10.1016/j.jmb.2017.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28827148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28827148"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Fengquan Dong, Cang Wu, Weipeng Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cryo-EM structure studies of the human VPS10 domain-containing receptor SorCS3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2022.07.009"}], "href": "https://doi.org/10.1016/j.bbrc.2022.07.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35940132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35940132"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Majid Alfadhel, Sarah Albahkali, Amani Almuaysib, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The SORCS3 gene is mutated in brothers with infantile spasms and intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Discov Med (2018)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30586538"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30586538"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yanqiu Zhang, Yue Li, Yuhua Fan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SorCS3 promotes the internalization of p75"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "NTR"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " to inhibit GBM progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-022-04753-5"}], "href": "https://doi.org/10.1038/s41419-022-04753-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35393432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35393432"}]}]}]}