Defective GNE does not hydrolyse UDP-GlcNAc

Stable Identifier
Reaction [transition]
Homo sapiens
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Bifunctional UDP-N-acetylglucosamine 2-epimerase, N-acetylmannosamine kinase (GNE) is a cytosolic enzyme involved in the first two critical, rate-limiting steps of sialic acid (Neu5Ac, N-acetylneuraminic acid) biosynthesis, a main constituent of glycoconjugates. In the first step, GNE normally hydrolyses and epimerises UDP-N-acetylglucosamine (UDP-GlcNAc) to N-acetylmannosamine (ManNAc). There are three disorders associated with defects in the GNE gene. Defects in GNE can cause sialuria (MIM:269921), an inborn error of metabolism characterised by cytoplasmic accumulation and increased urinary excretion of Neu5Ac. Mutations causing sialuria are R266W, R266Q and R263L (Seppala et al. 1999). Defects in GNE can also cause hereditary inclusion body myopathy (IBM2; MIM:600737), an autosomal recessive neuromuscular disorder characterised by adult-onset, progressive distal and proximal muscle weakness and wastage. The common M712T mutation can cause IBM2, as well as heterozygosity with the mutation M171V (Eisenberg et al. 2001, Argov et al. 2003, Broccolini et al. 2002). Defects in GNE can also cause Nonaka myopathy (NM; MIM:605820), an early adulthood-onset muscular disorder characterised by weakness and wastage of the lower limbs and rimmed vacuoles (Nonaka et al. 1981). Mutations causing NK include the common V572L, either homozygous or heterozygous with C303V (Tomimitsu et al. 2002, Kayashima et al. 2002) and the heterozygous M712T with A631V indicated that NK and IBM2 are allelic, if not identical, disorders (Tomimitsu et al. 2004).
Literature References
PubMed ID Title Journal Year
7252518 Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation

Ishiura, S, Nonaka, I, Sunohara, N, Satoyoshi, E

J. Neurol. Sci. 1981
11528398 The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy

Argov, Z, Grabov-Nardini, G, Mitrani-Rosenbaum, S, Shemesh, M, Olender, T, Chen, M, Lancet, D, Avidan, N, Eisenberg, I, Beckmann, JS, Karpati, G, Barash, M, Potikha, T, Friedmann, A, Bradley, WG, Hochner, H, Baumbach, L, Sadeh, M, Asher, EB, Shmilevich, I

Nat. Genet. 2001
12473780 An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene

D'Amico, A, Pescatori, M, Tonali, PA, Sabino, A, Broccolini, A, Silvestri, G, Ricci, E, Mirabella, M, Servidei, S

Neurology 2002
11916006 Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE)

Yoshiura, K, Kishino, T, Satoh, A, Niikawa, N, Nakane, Y, Ohta, T, Kayashima, T, Matsumoto, N, Matsuo, H

J. Hum. Genet. 2002
12743242 Hereditary inclusion body myopathy: the Middle Eastern genetic cluster

Eisenberg, I, Wirguin, I, Argov, Z, Grabov-Nardini, G, Mitrani-Rosenbaum, S, Soffer, D, Sadeh, M

Neurology 2003
12177386 Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene

Kanazawa, I, Ishikawa, K, Shimizu, J, Ohkoshi, N, Tomimitsu, H, Mizusawa, H

Neurology 2002
10330343 Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme

Lehto, VP, Seppala, R, Gahl, WA

Am. J. Hum. Genet. 1999
15136692 Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant

Kanazawa, I, Ishikawa, K, Shimizu, J, Ohkoshi, N, Tomimitsu, H, Mizusawa, H

Neurology 2004
Catalyst Activity

UDP-N-acetylglucosamine 2-epimerase activity of GNE mutants [cytosol]

Normal reaction
Functional status

Loss of function of GNE mutants [cytosol]

Name Identifier Synonyms
sialuria DOID:3659
inclusion body myositis DOID:3429 Inclusion body myositis (disorder), inclusion body myositis
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