{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSUMF1 encodes the formylglycine‐generating enzyme (FGE), which is indispensable for the post‐translational activation of all sulfatases. FGE converts a conserved cysteine residue within the sulfatases’ active sites into formylglycine—a key catalytic determinant required for sulfate ester hydrolysis on diverse substrates. Structural and biochemical studies have revealed that FGE possesses a unique fold with a minimal secondary structure and utilizes a novel oxygenase mechanism that does not require a classical metal cofactor (although later work showed a copper cofactor enhances activity), thereby ensuring proper sulfatase function. Moreover, studies have demonstrated that a paralog, SUMF2, can interact with SUMF1 and modulate its stimulatory effect on sulfatases, adding an additional layer of regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDefective SUMF1 activity underlies multiple sulfatase deficiency (MSD), a lysosomal storage disorder in which a loss or severe reduction of sulfatase activities results in the accumulation of sulfated substrates. Multiple clinical and molecular studies have demonstrated that mutations in SUMF1—notably missense, nonsense, and splicing alterations—lead to impaired FGE stability and catalytic activity, thus causing the variable and multisystem phenotypes seen in MSD patients. Detailed analyses in patient fibroblasts and genetically engineered models have shown that the residual enzyme activity and protein stability of FGE are critical determinants of the severity and progression of MSD. Furthermore, SUMF1 activity can be enhanced by co-delivery with sulfatase cDNAs, supporting the development of gene therapy approaches for the disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central catalytic role, SUMF1 is subject to sophisticated regulation through intracellular trafficking, post‐translational processing, and interactions with other endoplasmic reticulum proteins. FGE undergoes furin‐mediated limited proteolysis and couples with chaperones such as protein disulfide isomerase and ERp44, which control its ER retention and secretion. Secreted FGE can be taken up by distant cells, potentially enhancing sulfatase activity in gene therapy settings. Recent investigations have also raised the possibility that SUMF1 plays roles in other physiological and pathological contexts, with altered expression being linked to conditions such as chronic obstructive pulmonary disease, aspects of neuroinflammation, COVID-19, and even glioma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maria Pia Cosma, Stefano Pepe, Giancarlo Parenti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.20040"}], "href": "https://doi.org/10.1002/humu.20040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15146462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15146462"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Andrea Preusser-Kunze, Malaiyalam Mariappan, Bernhard Schmidt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular characterization of the human Calpha-formylglycine-generating enzyme."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413383200"}], "href": "https://doi.org/10.1074/jbc.M413383200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15657036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15657036"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Thomas Dierks, Achim Dickmanns, Andrea Preusser-Kunze, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2005.03.001"}], "href": "https://doi.org/10.1016/j.cell.2005.03.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15907468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15907468"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ester Zito, Alessandro Fraldi, Stefano Pepe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sulphatase activities are regulated by the interaction of sulphatase-modifying factor 1 with SUMF2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.embor.7400454"}], "href": "https://doi.org/10.1038/sj.embor.7400454"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15962010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15962010"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Alessandro Fraldi, Alessandra Biffi, Alessia Lombardi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20061783"}], "href": "https://doi.org/10.1042/BJ20061783"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17206939"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17206939"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Lars Schlotawa, Robert Steinfeld, Kurt von Figura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.9515"}], "href": "https://doi.org/10.1002/humu.9515"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18157819"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18157819"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Malaiyalam Mariappan, Karthikeyan Radhakrishnan, Thomas Dierks, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M709171200"}], "href": "https://doi.org/10.1074/jbc.M709171200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18178549"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18178549"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alessandro Fraldi, Ester Zito, Fabio Annunziata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddn161"}], "href": "https://doi.org/10.1093/hmg/ddn161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18508857"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18508857"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Uluç Yiş, Stefano Pepe, Semra Hiz Kurul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Dev (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.braindev.2007.10.007"}], "href": "https://doi.org/10.1016/j.braindev.2007.10.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18509892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18509892"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Lars Schlotawa, Eva Charlotte Ennemann, Karthikeyan Radhakrishnan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2010.219"}], "href": "https://doi.org/10.1038/ejhg.2010.219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21224894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21224894"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Lars Schlotawa, Michaela Wachs, Olaf Bernhard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.06.016"}], "href": "https://doi.org/10.1016/j.celrep.2018.06.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29972788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29972788"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Leen Hijazi, Amna Kashgari, Majid Alfadhel "}, {"type": "b", "children": [{"type": "t", "text": "Multiple Sulfatase Deficiency: A Case Series With a Novel Mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Child Neurol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0883073818790851"}], "href": "https://doi.org/10.1177/0883073818790851"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30124108"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30124108"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Lars Schlotawa, Laura A Adang, Karthikeyan Radhakrishnan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21103448"}], "href": "https://doi.org/10.3390/ijms21103448"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32414121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32414121"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Lars Schlotawa, Joana Preiskorn, Rebecca Ahrens-Nicklas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A systematic review and meta-analysis of published cases reveals the natural disease history in multiple sulfatase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jimd.12282"}], "href": "https://doi.org/10.1002/jimd.12282"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32621519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32621519"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Laura A Adang, Lars Schlotawa, Samuel Groeschel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jimd.12298"}], "href": "https://doi.org/10.1002/jimd.12298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32749716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32749716"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Patrick G Holder, Lesley C Jones, Penelope M Drake, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reconstitution of Formylglycine-generating Enzyme with Copper(II) for Aldehyde Tag Conversion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.652669"}], "href": "https://doi.org/10.1074/jbc.M115.652669"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25931126"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25931126"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Julie Weidner, Linnea Jarenbäck, Kim de Jong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Respir Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12931-017-0562-5"}], "href": "https://doi.org/10.1186/s12931-017-0562-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28464818"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28464818"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Anette Carolina Orjuela Leon, Anne Marwosky, Michael Arand "}, {"type": "b", "children": [{"type": "t", "text": "Evidence for a complex formation between CYP2J5 and mEH in living cells by FRET analysis of membrane protein interaction in the endoplasmic reticulum (FAMPIR)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Toxicol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00204-017-2072-0"}], "href": "https://doi.org/10.1007/s00204-017-2072-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29030652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29030652"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Shaohui Liang, Huixia Gao, Tongxin He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between SUMF1 polymorphisms and COVID-19 severity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Genom Data (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12863-023-01133-6"}], "href": "https://doi.org/10.1186/s12863-023-01133-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37344788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37344788"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Ping Zhang, Zhao Liu, Yu-Yu Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SUMF1 overexpression promotes tumorous cell growth and migration and is correlated with the immune status of patients with glioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging (Albany NY) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/aging.205626"}], "href": "https://doi.org/10.18632/aging.205626"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38460946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38460946"}]}]}]}