4zht

Structural highlights

Disease

[GLCNE_HUMAN] Defects in GNE are a cause of sialuria (SIALURIA) [MIM:269921]; also known as sialuria French type. In sialuria, free sialic acid accumulates in the cytoplasm and gram quantities of neuraminic acid are secreted in the urine. The metabolic defect involves lack of feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac, resulting in constitutive overproduction of free Neu5Ac. Clinical features include variable degrees of developmental delay, coarse facial features and hepatomegaly. Sialuria inheritance is autosomal dominant.^{[1] [2] [3] [4]} Defects in GNE are the cause of inclusion body myopathy type 2 (IBM2) [MIM:600737]. Hereditary inclusion body myopathies are a group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. IBM2 is an autosomal recessive disorder affecting mainly leg muscles, but with an unusual distribution that spares the quadriceps as also observed in Nonaka myopathy.^{[5] [6] [7] [8] [9] [10] [11]} Defects in GNE are the cause of Nonaka myopathy (NM) [MIM:605820]; also known as distal myopathy with rimmed vacuoles (DMRV). NM is an autosomal recessive muscular disorder, allelic to inclusion body myopathy 2. It is characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood, and sparing of the quadriceps muscles. As the inclusion body myopathy, NM is histologically characterized by the presence of numerous rimmed vacuoles without inflammatory changes in muscle specimens.^{[12] [13] [14] [15] [16]}

Function

[GLCNE_HUMAN] Regulates and initiates biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. Plays an essential role in early development (By similarity). Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells.^[17]

References

1. ↑ Weiss P, Tietze F, Gahl WA, Seppala R, Ashwell G. Identification of the metabolic defect in sialuria. J Biol Chem. 1989 Oct 25;264(30):17635-6. PMID:2808337
2. ↑ 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. PMID:10330343 doi:S0002-9297(07)63658-1
3. ↑ Ferreira H, Seppala R, Pinto R, Huizing M, Martins E, Braga AC, Gomes L, Krasnewich DM, Sa Miranda MC, Gahl WA. Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics. Mol Genet Metab. 1999 Jun;67(2):131-7. PMID:10356312 doi:10.1006/mgme.1999.2852
4. ↑ Leroy JG, Seppala R, Huizing M, Dacremont G, De Simpel H, Van Coster RN, Orvisky E, Krasnewich DM, Gahl WA. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am J Hum Genet. 2001 Jun;68(6):1419-27. Epub 2001 Apr 18. PMID:11326336 doi:10.1086/320598
5. ↑ 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. PMID:11528398 doi:10.1038/ng718
6. ↑ Darvish D, Vahedifar P, Huo Y. Four novel mutations associated with autosomal recessive inclusion body myopathy (MIM: 600737). Mol Genet Metab. 2002 Nov;77(3):252-6. PMID:12409274
7. ↑ Vasconcelos OM, Raju R, Dalakas MC. GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. Neurology. 2002 Dec 10;59(11):1776-9. PMID:12473769
8. ↑ Broccolini A, Pescatori M, D'Amico A, Sabino A, Silvestri G, Ricci E, Servidei S, Tonali PA, Mirabella M. An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene. Neurology. 2002 Dec 10;59(11):1808-9. PMID:12473780
9. ↑ 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. PMID:12497639 doi:10.1002/humu.9100
10. ↑ Del Bo R, Baron P, Prelle A, Serafini M, Moggio M, Fonzo AD, Castagni M, Bresolin N, Comi GP. Novel missense mutation and large deletion of GNE gene in autosomal-recessive inclusion-body myopathy. Muscle Nerve. 2003 Jul;28(1):113-7. PMID:12811782 doi:10.1002/mus.10391
11. ↑ Broccolini A, Ricci E, Cassandrini D, Gliubizzi C, Bruno C, Tonoli E, Silvestri G, Pescatori M, Rodolico C, Sinicropi S, Servidei S, Zara F, Minetti C, Tonali PA, Mirabella M. Novel GNE mutations in Italian families with autosomal recessive hereditary inclusion-body myopathy. Hum Mutat. 2004 Jun;23(6):632. PMID:15146476 doi:10.1002/humu.9252
12. ↑ Arai A, Tanaka K, Ikeuchi T, Igarashi S, Kobayashi H, Asaka T, Date H, Saito M, Tanaka H, Kawasaki S, Uyama E, Mizusawa H, Fukuhara N, Tsuji S. A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees. Ann Neurol. 2002 Oct;52(4):516-9. PMID:12325084 doi:10.1002/ana.10341
13. ↑ 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. PMID:11916006 doi:10.1007/s100380200004
14. ↑ Tomimitsu H, Ishikawa K, Shimizu J, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. Neurology. 2002 Aug 13;59(3):451-4. PMID:12177386
15. ↑ Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, Nagata T, Chida K, Takahashi T, Takusa Y, Ohi T, Nishimiya J, Sunohara N, Ciafaloni E, Kawai M, Aoki M, Nonaka I. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology. 2002 Dec 10;59(11):1689-93. PMID:12473753
16. ↑ Yabe I, Higashi T, Kikuchi S, Sasaki H, Fukazawa T, Yoshida K, Tashiro K. GNE mutations causing distal myopathy with rimmed vacuoles with inflammation. Neurology. 2003 Aug 12;61(3):384-6. PMID:12913203
17. ↑ 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. PMID:10334995