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URL of this page: https://medlineplus.gov/genetics/gene/gne/

GNE gene

glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase

Normal Function

The GNE gene provides instructions for making an enzyme that is found in cells and tissues throughout the body. This enzyme plays a key role in a chemical pathway that produces sialic acid, which is a simple sugar that attaches to the ends of more complex molecules on the surface of cells. By modifying these molecules, sialic acid influences a wide variety of cellular functions, including cell movement (migration), the attachment of cells to one another (adhesion), signaling between cells, and inflammation.

The enzyme produced from the GNE gene is responsible for two steps in the formation of sialic acid. It first converts a molecule known as UDP-GlcNAc (UDP-N-acetylglucosamine) to a similar molecule called ManNAc (N-acetylmannosamine). In the next step, the enzyme transfers a cluster of oxygen and phosphorus atoms (a phosphate group) to ManNAc to create ManNAc-6-phosphate. Other enzymes then convert ManNAc-6-phosphate to sialic acid.

Health Conditions Related to Genetic Changes

GNE myopathy

Variants (also called mutations) in the GNE gene can cause GNE myopathy, a condition that leads to progressive muscle weakness in adults. Many different variants in the gene have been found in people with GNE myopathy. Most of these variants change single protein building blocks (amino acids) in several regions of the enzyme. A few variants delete a piece of the enzyme or otherwise alter its structure.

Different GNE variants cause GNE myopathy in different populations. One variant is more frequent in people of Iranian Jewish heritage; this genetic change replaces the amino acid methionine with the amino acid threonine at position 743 in a region of the enzyme known as the kinase domain (written as Met743Thr or M743T). In the Japanese population, there are three common GNE variants that affect amino acids 44, 207, and 603 (written as C44S, D207V, and V603L).

The variants responsible for GNE myopathy reduce the activity of the enzyme produced from the GNE gene, which decreases the production of sialic acid. As a result, less of this simple sugar is available to attach to molecules on the cell surface. Researchers are working to determine how a shortage of sialic acid leads to progressive muscle weakness in people with GNE myopathy. Sialic acid is important for the normal function of many different cells and tissues, so it is unclear why the signs and symptoms of this disorder appear to be limited to skeletal muscles.

More About This Health Condition

Sialuria

Several variants in the GNE gene have been found to cause sialuria. Each of these variants changes a single amino acid in a region of the enzyme known as the allosteric site. This region is critical for the normal regulation of the enzyme.

A feedback system helps control the amount of sialic acid produced in cells. This system shuts off the enzyme produced from the GNE gene when no more sialic acid is needed. Variants in the allosteric site can disrupt this feedback mechanism, resulting in an overproduction of sialic acid. This simple sugar builds up within cells and is excreted in urine. Researchers are working to determine how an accumulation of sialic acid in the body interferes with normal development in people with sialuria.

More About This Health Condition

Other Disorders

Some people with GNE variants have been found to have a lower number of platelets (thrombocytopenia), a condition called GNE-related thrombocytopenia. When variants in the GNE gene reduce the function of the enzyme produced by the GNE gene, platelets have less sialic acid. This lack of sialic acid causes the liver to remove platelets from the blood more quickly, resulting in a lower number of platelets.

A lower number of platelets may cause bleeding issues in people with GNE-related thrombocytopenia. Muscle weakness (myopathy) has also been reported in some individuals.



Other Names for This Gene

  • Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
  • DMRV
  • GLCNE
  • IBM2
  • Uae1
  • UDP-GlcNAc-2-epimerase/ManAc kinase
  • UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

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  • Carrillo N, Malicdan MC, Huizing M. GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges. Neurotherapeutics. 2018 Oct;15(4):900-914. doi: 10.1007/s13311-018-0671-y. Citation on PubMed
  • Celeste FV, Vilboux T, Ciccone C, de Dios JK, Malicdan MC, Leoyklang P, McKew JC, Gahl WA, Carrillo-Carrasco N, Huizing M. Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat. 2014 Aug;35(8):915-26. doi: 10.1002/humu.22583. Citation on PubMed
  • Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet. 2001 Sep;29(1):83-7. doi: 10.1038/ng718. Citation on PubMed
  • Eisenberg I, Grabov-Nardini G, Hochner H, Korner M, Sadeh M, Bertorini T, Bushby K, Castellan C, Felice K, Mendell J, Merlini L, Shilling C, Wirguin I, Argov Z, Mitrani-Rosenbaum S. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat. 2003 Jan;21(1):99. doi: 10.1002/humu.9100. Citation on PubMed
  • Futterer J, Dalby A, Lowe GC, Johnson B, Simpson MA, Motwani J, Williams M, Watson SP, Morgan NV; UK GAPP Study Group. Mutation in GNE is associated with severe congenital thrombocytopenia. Blood. 2018 Oct 25;132(17):1855-1858. doi: 10.1182/blood-2018-04-847798. Epub 2018 Jun 25. No abstract available. Citation on PubMed
  • Kayashima T, Matsuo H, Satoh A, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Niikawa N, Kishino T. Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). J Hum Genet. 2002;47(2):77-9. doi: 10.1007/s100380200004. Citation on PubMed
  • Keppler OT, Hinderlich S, Langner J, Schwartz-Albiez R, Reutter W, Pawlita M. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science. 1999 May 21;284(5418):1372-6. doi: 10.1126/science.284.5418.1372. Citation on PubMed
  • Klootwijk RD, Savelkoul PJ, Ciccone C, Manoli I, Caplen NJ, Krasnewich DM, Gahl WA, Huizing M. Allele-specific silencing of the dominant disease allele in sialuria by RNA interference. FASEB J. 2008 Nov;22(11):3846-52. doi: 10.1096/fj.08-110890. Epub 2008 Jul 24. Citation on PubMed or Free article on PubMed Central
  • Krause S, Aleo A, Hinderlich S, Merlini L, Tournev I, Walter MC, Argov Z, Mitrani-Rosenbaum S, Lochmuller H. GNE protein expression and subcellular distribution are unaltered in HIBM. Neurology. 2007 Aug 14;69(7):655-9. doi: 10.1212/01.wnl.0000267426.97138.fd. Citation on PubMed
  • Malicdan MC, Noguchi S, Nishino I. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Curr Opin Neurol. 2008 Oct;21(5):596-600. doi: 10.1097/WCO.0b013e32830dd595. Citation on PubMed
  • Mullen J, Alrasheed K, Mozaffar T. GNE myopathy: History, etiology, and treatment trials. Front Neurol. 2022 Oct 18;13:1002310. doi: 10.3389/fneur.2022.1002310. eCollection 2022. Citation on PubMed
  • Nishino I, Malicdan MC, Murayama K, Nonaka I, Hayashi YK, Noguchi S. Molecular pathomechanism of distal myopathy with rimmed vacuoles. Acta Myol. 2005 Oct;24(2):80-3. Citation on PubMed
  • Noguchi S, Keira Y, Murayama K, Ogawa M, Fujita M, Kawahara G, Oya Y, Imazawa M, Goto Y, Hayashi YK, Nonaka I, Nishino I. Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem. 2004 Mar 19;279(12):11402-7. doi: 10.1074/jbc.M313171200. Epub 2004 Jan 5. Citation on PubMed
  • Penner J, Mantey LR, Elgavish S, Ghaderi D, Cirak S, Berger M, Krause S, Lucka L, Voit T, Mitrani-Rosenbaum S, Hinderlich S. Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy. Biochemistry. 2006 Mar 7;45(9):2968-77. doi: 10.1021/bi0522504. Citation on PubMed
  • Revel-Vilk S, Shai E, Turro E, Jahshan N, Hi-Am E, Spectre G, Daum H, Kalish Y, Althaus K, Greinacher A, Kaplinsky C, Izraeli S, Mapeta R, Deevi SVV, Jarocha D, Ouwehand WH, Downes K, Poncz M, Varon D, Lambert MP. GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting. Blood. 2018 Oct 25;132(17):1851-1854. doi: 10.1182/blood-2018-04-845545. Epub 2018 Aug 31. No abstract available. Citation on PubMed
  • Seppala R, Lehto VP, Gahl WA. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am J Hum Genet. 1999 Jun;64(6):1563-9. doi: 10.1086/302411. Citation on PubMed or Free article on PubMed Central
  • Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. Neurology. 2004 May 11;62(9):1607-10. doi: 10.1212/01.wnl.0000123115.23652.6c. Citation on PubMed
  • Wopereis S, Abd Hamid UM, Critchley A, Royle L, Dwek RA, Morava E, Leroy JG, Wilcken B, Lagerwerf AJ, Huijben KM, Lefeber DJ, Rudd PM, Wevers RA. Abnormal glycosylation with hypersialylated O-glycans in patients with Sialuria. Biochim Biophys Acta. 2006 Jun;1762(6):598-607. doi: 10.1016/j.bbadis.2006.03.009. Citation on PubMed

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.