{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genome‐wide association studies have implicated TMEM163 in type 2 diabetes pathogenesis, where fine‐mapping of the 2q21 locus revealed that TMEM163 encodes a probable vesicular transporter in nerve terminals. Altered TMEM163 expression is associated with decreased fasting insulin levels and impaired insulin secretion, suggesting that dysregulation of intracellular zinc may contribute to β‐cell dysfunction. These observations are further supported by replication studies showing that reduced TMEM163 in pancreatic cells leads to increased intracellular zinc, elevated total insulin content, and altered glucose uptake, thereby linking TMEM163 function to metabolic homeostasis."}, {"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": "\nBiochemical and cellular studies have further characterized TMEM163 as a zinc transporter that maintains cellular zinc homeostasis. It physically interacts with the TRPML1 ion channel—a link that may underlie zinc mislocalization in disorders such as mucolipidosis type IV—and functions predominantly as a zinc efflux transporter. Functional analyses employing site‐directed mutagenesis of conserved aspartate residues confirm that these residues are critical for zinc transport activity. In addition, investigations in platelets have identified TMEM163 as a key component in dense granule biogenesis, with its proper trafficking via the BLOC-1 complex being required to prevent abnormal zinc accumulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in metabolic and secretory pathways, TMEM163 has emerged as a candidate risk factor in neurodegenerative disorders. Rare variants in TMEM163 have been associated with early-onset Parkinson’s disease, and recent studies in oligodendroglial models demonstrate that dysfunctional zinc efflux due to TMEM163 mutations can lead to reduced expression of key myelin genes, impaired cellular branching, and increased cell death. These findings suggest that TMEM163 not only regulates zinc homeostasis in diverse tissues but also plays a critical role in neural development and myelin formation, thereby extending its significance to central nervous system homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rubina Tabassum, Ganesh Chauhan, Om Prakash Dwivedi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Transmembrane 163 (TMEM163) protein effluxes zinc."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2019.108166"}], "href": "https://doi.org/10.1016/j.abb.2019.108166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31697912"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31697912"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yefeng Yuan, Teng Liu, Xiahe Huang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Functional Study of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "TMEM163"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Gene Variants Associated with Hypomyelination Leukodystrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells11081285"}], "href": "https://doi.org/10.3390/cells11081285"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35455965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35455965"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Michelle C do Rosario, Guillermo Rodriguez Bey, Bruce Nmezi, et al. 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