{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM199 was first identified as an uncharacterized transmembrane protein that functions as a V‐ATPase assembly factor, analogous to the yeast Vph2p. Disruption of TMEM199 impairs the acidification of endo‐lysosomal compartments, leading to intracellular iron depletion that in turn compromises the activity of 2-oxoglutarate and iron(II) prolyl hydroxylase enzymes. This impaired hydroxylation of HIF1α stabilizes the transcription factor even in normoxic conditions, revealing a novel regulatory link between V-ATPase function, iron metabolism, and oxygen sensing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSubsequent research identified TMEM199 as the human homolog of yeast Vph2p and highlighted its critical role in maintaining Golgi homeostasis. Mutations in TMEM199 disrupt normal protein glycosylation, resulting in defects in both N- and mucin-type O-glycan processing. Affected individuals exhibit a congenital disorder of glycosylation characterized by hepatic steatosis, elevated aminotransferases, altered lipid profiles, and reduced serum ceruloplasmin—a phenotype that underscores the importance of proper Golgi function for protein modification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations employing human plasma analyses, cellular models, and a mouse model have demonstrated that mutations in TMEM199 provoke broader metabolic disturbances. Notably, these studies have established that TMEM199 deficiency is associated with hypercholesterolemia and the development of fatty liver disease, thereby linking its disruption to abnormalities in lipid metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA further clinical characterization of TMEM199 deficiency has delineated a congenital disorder of glycosylation (TMEM199-CDG) that primarily manifests as a non-encephalopathic liver disease with features reminiscent of Wilson disease. Patients carrying the recurrent p.Arg31Pro mutation consistently display mild, non-progressive hepatopathy alongside biochemical alterations in copper and glycosylation profiles, reinforcing the pivotal role of TMEM199 in preserving Golgi integrity and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anna L Miles, Stephen P Burr, Guinevere L Grice, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.22693"}], "href": "https://doi.org/10.7554/eLife.22693"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28296633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28296633"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jos C Jansen, Sharita Timal, Monique van Scherpenzeel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2015.12.011"}], "href": "https://doi.org/10.1016/j.ajhg.2015.12.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26833330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26833330"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lars E Larsen, Marjolein A W van den Boogert, Wilson A Rios-Ocampo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective Lipid Droplet-Lysosome Interaction Causes Fatty Liver Disease as Evidenced by Human Mutations in TMEM199 and CCDC115."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Gastroenterol Hepatol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jcmgh.2021.09.013"}], "href": "https://doi.org/10.1016/j.jcmgh.2021.09.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34626841"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34626841"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Agata Fiumara, Annamaria Sapuppo, Lorenzo Ferri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2023.104709"}], "href": "https://doi.org/10.1016/j.ejmg.2023.104709"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36706865"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36706865"}]}]}]}