Disease relevance of GNE

• Clinical and genetic heterogeneity in chromosome 9p associated hereditary inclusion body myopathy: exclusion of GNE and three other candidate genes [1].
• Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene [2].
• These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations [3].
• Mutations associated with sialuria are located in the epimerase domain, and those associated with IBM2 are in the epimerase or the kinase domain or both, whereas the mutations we observed in the Nonaka myopathy patients were located in the sugar kinase domain of the gene [4].
• A 6th gene, GNE, responsible for the hereditary form of inclusion body myositis, encodes for a glycosyltransferase the substrate(s) of which is, however, still unclear [5].

Psychiatry related information on GNE

• Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2 [6].

High impact information on GNE

• This comprehensive study of downstream molecular consequences of NM gene mutations provides insights in the cellular events leading to the NM phenotype [7].
• Using Affymetrix oligonucleotide microarrays, we have analyzed the expression patterns of >21,000 genes and expressed sequence tags in skeletal muscles of 12 NM patients and 21 controls [7].
• We report the identification of high satellite cell populations in NM and the significant down-regulation of transcripts for key enzymes of glucose and glycogen metabolism as well as a possible regulator of fatty acid metabolism, UCP3 [7].
• Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion myopathy (h-IBM) is an early adult-onset distal myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene which encodes for a bifunctional enzyme involved in sialic acid biosynthesis [8].
• The UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM) [9].

Chemical compound and disease context of GNE

• The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene is the causative gene for autosomal-recessive hereditary inclusion-body myopathy (h-IBM) [10].
• Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness [3].
• Lec3 mutants with no UDP-GlcNAc 2-epimerase activity represent sensitive hosts for characterizing disease-causing mutations in the human GNE gene that give rise to sialuria, hereditary inclusion body myopathy, and Nonaka myopathy [11].

Biological context of GNE

• A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees [9].
• To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees [9].
• The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles [2].
• The bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) is essential for early embryonic development and catalyzes the rate limiting step in sialic acid biosynthesis [12].
• These results indicate that although mutations in each of the two GNE domains result in an impaired enzymatic activity and the same HIBM phenotype, they do not equally affect the overall sialylation of muscle cells [13].

Anatomical context of GNE

• In human skeletal muscle, GNE protein is developmentally regulated: high levels are found in immature myoblasts but low levels in mature skeletal muscle [12].
• Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells [12].
• Fibroblasts exhibited higher residual activities of both GNE and MNK than the cell-free system [14].
• While all myoblasts carrying a mutated GNE gene show a reduction in their epimerase activity, only the cells derived from the patient carrying a homozygous epimerase mutation present also a significant reduction in the overall membrane bound sialic acid [13].
• In order to investigate the consequences of the mutated GNE enzyme in muscle cells, we have established cell cultures from muscle biopsies carrying either kinase or epimerase mutations [13].

Associations of GNE with chemical compounds

• Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) [15].
• This subcellular localization of GNE is in good agreement with its established role as the key enzyme of sialic acid biosynthesis, since the sialylation of glycoconjugates takes place in the Golgi complex [12].
• Upon nocodazole treatment, GNE redistributes to the cytoplasm suggesting that GNE may act as a nucleocytoplasmic shuttling protein [12].
• AR hIBM is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene on chromosome 9p12-13 . We report two unrelated Tunisian families with clinical and pathological features of AR HIBM [16].
• A novel homozygous G-to-A mutation (128933G-->A) in exon 7 changing a valine to isoleucine (V367I) in the epimerase domain of the GNE gene was found [17].

Other interactions of GNE

• Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic [1].
• Parallel to this study, the gene termed GNE, approximately 50 kb centromeric to C9orf19, was shown to be the disease causing gene in IBM2 [18].
• The RNF38 genomic structure was determined and comprises at least 13 exons extending over more than 65 kb in the genome, 78 kb centromeric to the GNE gene on human chromosome 9p12-p13 [19].
• Late-onset distal myopathy with rimmed vacuoles without mutation in the GNE or dysferlin genes [20].
• NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE mutations [21].

Analytical, diagnostic and therapeutic context of GNE

• Using a human prey matrix we identified four proteins interacting with GNE in a yeast two-hybrid assay [22].

References