{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVPS16 is a critical component of the multisubunit HOPS and CORVET tethering complexes, playing an essential role in endolysosomal and autophagosomal membrane fusion. Structural studies have revealed that VPS16 recruits the Sec1/Munc18 family member VPS33A via a defined binding region, thereby providing a framework for the timely fusion of late endosomes, autophagosomes, and lysosomes, which is vital for efficient intracellular trafficking and degradation processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic investigations in patients with suspected dystonia have increasingly implicated VPS16 in the pathogenesis of movement disorders. In particular, mutations—including homozygous missense and frameshift variants—have been associated with adolescent-onset primary dystonia and early-onset multifocal forms, as supported by patient analyses and corresponding animal models. These findings highlight that VPS16 dysfunction may underlie previously undiagnosed cases of genetic dystonia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in neural function, VPS16 mutations can impair intracellular trafficking to an extent that causes multisystem storage disorders reminiscent of mucopolysaccharidosis. An intronic variant that decreases VPS16 expression not only disrupts endosomal trafficking—resulting in the accumulation of autophagosomes and lysosomal compartments in patient-derived cells and zebrafish models—but also destabilizes other HOPS/CORVET subunits, thereby expanding the spectrum of diseases linked to defects in this tethering machinery."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cellular trafficking and neurological disease, VPS16 has emerged as a relevant factor in tumorigenesis. Overexpression of VPS16 has been observed in colorectal cancer, where it facilitates autolysosomal maturation to promote cell survival and mediate chemoresistance, and its dysregulation has also been implicated in liver hepatocellular carcinoma. Such findings point toward a broader function for VPS16 in maintaining cellular homeostasis and impacting disease outcomes across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephen C Graham, Lena Wartosch, Sally R Gray, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.25879"}], "href": "https://doi.org/10.1002/ana.25879"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32808683"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32808683"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaodong Cai, Xin Chen, Song Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep25834"}], "href": "https://doi.org/10.1038/srep25834"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27174565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27174565"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Li-Xi Li, Li-Ting Jiang, Ying Liu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mov Disord Clin Pract (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mdc3.13927"}], "href": "https://doi.org/10.1002/mdc3.13927"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38291845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38291845"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kalliopi Sofou, Kolja Meier, Leslie E Sanderson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/emmm.202013376"}], "href": "https://doi.org/10.15252/emmm.202013376"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33938619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33938619"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yılmaz Yıldız, Can Koşukcu, Damla Aygün, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.14002"}], "href": "https://doi.org/10.1111/cge.14002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34013567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34013567"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Baoqing Zhang, Yuanyuan Ma, Huanmin Niu, et al. 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