{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:06:27Z","timestamp":1792033587068,"version":"4.4.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T00:00:00Z","timestamp":1705276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["2155"],"award-info":[{"award-number":["2155"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["460683975"],"award-info":[{"award-number":["460683975"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>GNE myopathy (GNEM) is a late-onset muscle atrophy, caused by mutations in the gene for the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase\/N-acetylmannosamine kinase (GNE). With an incidence of one to nine cases per million it is an ultra-rare, so far untreatable, autosomal recessive disease. Several attempts have been made to treat GNEM patients by oral supplementation with sialic acid precursors (e.g. N-acetylmannosamine, ManNAc) to restore sarcolemmal sialylation and muscle strength. In most studies, however, no significant improvement was observed. The lack of a suitable mouse model makes it difficult to understand the exact pathomechanism of GNEM and many years of research have failed to identify the role of GNE in skeletal muscle due to the lack of appropriate tools. We established a CRISPR\/Cas9-mediated Gne-knockout cell line using murine C2C12 cells to gain insight into the actual role of the GNE enzyme and sialylation in a muscular context. The main aspect of this study was to evaluate the therapeutic potential of ManNAc and N-acetylneuraminic acid (Neu5Ac). Treatment of Gne-deficient C2C12 cells with Neu5Ac, but not with ManNAc, showed a restoration of the sialylation level back to wild type levels\u2013albeit only with long-term treatment, which could explain the rather low therapeutic potential. We furthermore highlight the importance of sialic acids on myogenesis, for C2C12 Gne-knockout myoblasts lack the ability to differentiate into mature myotubes.<\/jats:p>","DOI":"10.1093\/glycob\/cwae004","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T15:12:10Z","timestamp":1705331530000},"source":"Crossref","is-referenced-by-count":11,"title":["GNE deficiency impairs Myogenesis in C2C12 cells and cannot be rescued by ManNAc supplementation"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3238-8541","authenticated-orcid":false,"given":"Carolin T","family":"Neu","sequence":"first","affiliation":[{"name":"Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg , 06114 Halle (Saale) , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linus","family":"Weilepp","sequence":"additional","affiliation":[{"name":"Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg , 06114 Halle (Saale) , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-9115","authenticated-orcid":false,"given":"Kaya","family":"Bork","sequence":"additional","affiliation":[{"name":"Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg , 06114 Halle (Saale) , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-9973","authenticated-orcid":false,"given":"Astrid","family":"Gesper","sequence":"additional","affiliation":[{"name":"Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg , 06114 Halle (Saale) , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Horstkorte","sequence":"additional","affiliation":[{"name":"Institute for Physiological Chemistry, Medical Faculty, Martin Luther University Halle-Wittenberg , 06114 Halle (Saale) , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,15]]},"reference":[{"issue":"10","key":"2024040301390351900_ref1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41570-019-0126-y","article-title":"Exploiting metabolic glycoengineering to advance healthcare","volume":"3","author":"Agatemor","year":"2019","journal-title":"Nat Rev Chem"},{"issue":"3","key":"2024040301390351900_ref2","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1042\/bj1850577","article-title":"Kinetic characterization of n-acetyl-d-glucosamine kinase from rat liver and kidney","volume":"185","author":"Allen","year":"1980","journal-title":"Biochem J"},{"issue":"1","key":"2024040301390351900_ref3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0022-510X(84)90053-4","article-title":"\"Rimmed vacuole myopathy\" sparing the quadriceps. A unique disorder in iranian jews","volume":"64","author":"Argov","year":"1984","journal-title":"J Neurol Sci"},{"issue":"2","key":"2024040301390351900_ref4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00418-016-1520-x","article-title":"Sialylation of n-glycans: mechanism, cellular compartmentalization and function","volume":"147","author":"Bhide","year":"2017","journal-title":"Histochem Cell Biol"},{"key":"2024040301390351900_ref5","doi-asserted-by":"crossref","first-page":"100030","DOI":"10.1074\/mcp.RA120.002166","article-title":"Integrated glycoproteomics identifies a role of n-glycosylation and galectin-1 on myogenesis and muscle development","volume":"20","author":"Blazev","year":"2021","journal-title":"Mol Cell Proteomics"},{"issue":"4","key":"2024040301390351900_ref6","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1007\/s13311-018-0671-y","article-title":"GNE myopathy: Etiology, diagnosis, and therapeutic challenges","volume":"15","author":"Carrillo","year":"2018","journal-title":"Neurotherapeutics"},{"key":"2024040301390351900_ref7","doi-asserted-by":"crossref","first-page":"669","DOI":"10.3389\/fnins.2018.00669","article-title":"Fighting the cause of alzheimer's and GNE myopathy","volume":"12","author":"Devi","year":"2018","journal-title":"Front Neurosci"},{"issue":"1","key":"2024040301390351900_ref8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/ng718","article-title":"The udp-n-acetylglucosamine 2-epimerase\/n-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy","volume":"29","author":"Eisenberg","year":"2001","journal-title":"Nat Genet"},{"issue":"13","key":"2024040301390351900_ref9","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1039\/D2SC06986E","article-title":"Real-time monitoring of the sialic acid biosynthesis pathway by nmr","volume":"14","author":"Gorenflos Lopez","year":"2023","journal-title":"Chem Sci"},{"issue":"39","key":"2024040301390351900_ref10","doi-asserted-by":"crossref","first-page":"24313","DOI":"10.1074\/jbc.272.39.24313","article-title":"A bifunctional enzyme catalyzes the first two steps in n-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of udp-n-acetylglucosamine 2-epimerase\/n-acetylmannosamine kinase","volume":"272","author":"Hinderlich","year":"1997","journal-title":"J Biol Chem"},{"issue":"2","key":"2024040301390351900_ref11","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1515\/BC.2001.036","article-title":"Biosynthesis of n-acetylneuraminic acid in cells lacking udp-n-acetylglucosamine 2-epimerase\/n-acetylmannosamine kinase","volume":"382","author":"Hinderlich","year":"2001","journal-title":"Biol Chem"},{"issue":"1\u20133","key":"2024040301390351900_ref12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.febslet.2004.04.013","article-title":"The homozygous m712t mutation of udp-n-acetylglucosamine 2-epimerase\/n-acetylmannosamine kinase results in reduced enzyme activities but not in altered overall cellular sialylation in hereditary inclusion body myopathy","volume":"566","author":"Hinderlich","year":"2004","journal-title":"FEBS Lett"},{"issue":"4","key":"2024040301390351900_ref13","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/09168451.2014.991682","article-title":"Autophagy regulates the stability of sialin, a lysosomal sialic acid transporter","volume":"79","author":"Huang","year":"2015","journal-title":"Biosci Biotechnol Biochem"},{"key":"2024040301390351900_ref14","doi-asserted-by":"crossref","DOI":"10.3389\/fgeed.2022.930110","article-title":"In vivo and in vitro genome editing to explore gne functions","volume":"4","author":"Ilouz","year":"2022","journal-title":"Front Genome Ed"},{"issue":"10","key":"2024040301390351900_ref15","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/S0960-8966(03)00140-8","article-title":"A novel homozygous missense mutation in the gne gene of a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation","volume":"13","author":"Krause","year":"2003","journal-title":"Neuromuscul 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