(last modified February 4, 2011)
generated with the help of the Hogeschool Leiden, in particular students Kars van der Weijden and Kevin van der Graaf
GNE (Glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) is located on chromosome 9p13.3, has a total length of 62 Kb and covers 12 exons. Through the use of two alternative promoter/first-exons and alternative splicing the gene generates 5 transcript variants, encoding 5 protein isoforms. The enzyme of Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase is involved in the production of sialic acid. Sialic acid is crucial for the function of biologic processes like signal transduction and cell adhesion. Variants in GNE have been shown to cause sialuria, IBM-2 (inclusion body myopathy type-2) and Nonaka myopathy.
Links to other databases:
Gene Symbol
nomenclature EntrezGene
OMIM Gene Map
The GNE gene (Gene symbol GNE, aliases DMRV, GLCNE, IBM2, Uae1) encodes the enzyme UDP-N-acetylglucosamine 2-epimerase / N-acetylmannosamine kinase. The gene maps to chromosome 9p13.3, is transcribed from centromere to telomere and is flanked by CTLA (telomeric, opposite transcriptional orientation) and RNF38 (centromeric, same transcriptional orientation). The GNE gene measures some 62 Kb (see GNE coding DNA Reference Sequence) and contains 13 exons amongst which two alternative promoter/first exons, designated exon 1 and exon 1b (located in intron 1). Alternative splicing of exons 2, 4 and 9 generates a range of transcripts and protein isoforms.
| Exon | Exon size (in bp) |
Intron size (in bp) |
5' cDNA position (in bp) | Splice after |
Remarks |
|---|---|---|---|---|---|
| 1 | 90 | 27,496 | -112 | 0 | 5'UTR, alternative translation initiation site GNE isoforms 3, translation initiation site GNE isoforms 1 |
| 1b | 122 | 8,923 | -70 | - | alternative promoters/first exon, 5'UTR |
| 2 | 206 | 2,709 | 52 | 2 | alternative spliced exon, translation initiation site GNE isoform 4 |
| 3 | 452 | 9,046 | 258 | 1 | translation initiation site GNE isoforms 2 and 5 |
| 4 | 153 | 2,699 | 710 | 1 | alternative spliced exon |
| 5 | 213 | 4,811 | 863 | 1 | |
| 6 | 88 | 1,562 | 1,076 | 2 | |
| 7 | 211 | 3,745 | 1,164 | 0 | |
| 8 | 130 | 374 | 1,375 | 1 | |
| 9 | 222 | 2,756 | 1,505 | 1 | alternative spliced exon |
| 10 | 183 | 1,538 | 1,727 | 1 | |
| 11 | 117 | 582 | 1,910 | 1 | |
| 12 | 3160 | - | 2,027 | - | translation stop codon, 3'UTR |
Legend:
Exon: numbering of exons with the first base of the Met-codon counted as position 1
(see coding DNA Reference
Sequence). Exon size: size of exon indicated in basepairs (bp). Intron size:
size of intron indicated in basepairs. 5' cDNA position: first base of the exon. Splice
after: splicing occurs in between of two coding triplets (0), after the first (1) or
the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated region, 3'UTR =
3' untranslated region.
Links to other databases: UniGene: Hs.5920 RefSeq: NM_001128227.2
Due to the use of two promoter/first exons and alternative splicing (exons 2, 4 and 9) the GNE generates a range of transcript variants. Five of these have been characterised in more detail, variant-2 is referred to in most studies. Transcript variant-3 skips exon 2 and uses an alternative translation initiation site (and reading frame) in exon 1, encoding protein isoform-3. Transcript variants-2, -4 and -5 use the alternative promoter/first exon located in intron 1. Transcript variant-2 skips exon 9 and initiates translation in exon 2 (encoding protein isoform-3). Transcript variant-4 skips exon 9 and uses a translation initiation site in exon 2 (encoding protein isoform-4). Isoform 5 skips exons 2 and 4, and initiates translation in exon 3.
The GNE (transcript variant-2) is ubiquitously expressed. Highest expression levels are found in the liver and placenta. Lower concentrations are detectable in muscle, brain, kidney, pancreas and fibroblasts.
Links to other databases: RefSeq: NP_001121699.1 UniProt: P24534
The GNE isoform-1 is a 753 amino acid protein, isoform-2 consists of 722 amino acids (molecular weight of 79,275 daltons, Stäsche [1997]).
Multiple protein sequence alignment for GNE
GNE is the enzyme UDP-N-acetylglucosamine 2-epimerase, regulating the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. In the first step, the bifunctional enzyme catalyses the conversion of UDP-GlcNAc to ManNAc. In the second step, it converts ManNAc into ManNAc-6-phosphate by adding a phosphate group (Effertz [1999]). Other enzymes are involved for the creation of sialic acid from ManNac-6-phosphate. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including signal transduction and cell adhesion. The differential of sialylation of cell surface molecules is also implicated in the metastatic behavior of malignant cells and tumorgenicity (Effertz [1999]).
Links to other databases: OMIM: 269921, 600737 and 605820
Variations in the GNE were found to be associated with DMRV was reported by (Nonaka 1981), IBM-2 (Argov 1984) and sialuria (Seppala 1999). Variants associated with sialuria are located in the epimerase domain, those associated with IBM-2 in the epimerase or kinase domain or both. In Nonaka myopathy variants are located in the sugar kinase domain (Kayashima 2002)
Sialuria, originally described by Montreuil (1968) and Fontaine (1968), is characterised by massive excretion of free sialic acid. GNE was identified as the causative gene by Seppala (1999) after cloning and sequencing the human cDNA in controls and three sialuria patients. They identified three dominantly inherited variants in codons 263 (Arg263Leu) and codon 266 (Arg266Trp and Arg266Gln), which indicated that the allosteric site of the epimerase resides in this regions. When sialic acid is not required, a feedback system stops its production. When the allosteric site is mutated, this feedback mechanism is disrupted, resulting in a continuous production of sialic acid. This ultimately leads to excretion of the sugar in urine (Kamerling [1979]).
Inclusion body myopathy type-2 (IBM-2) is a second disorder caused by variants in the GNE gene first found in Jews of Persian origin (Argov 1984). It is inherited in an autosomal recessive way and disease onset occurs after 20 years but before mid 4th decade of life. The disorder starts with mainly leg muscle weakness and most patients become incapacitated a decade after onset. A unique feature of this form of IBM is the sparing of quadriceps muscles (QSM). This disorder was mapped to 9p13-p12. Eisenberg (2001) identified in 104 affected persons from 47 Middle Eastern families the same GNE-variant in homozygous. Affected individuals of other ethnic origins were mostly found to be compound heterozygotes for other variants in the GNE gene.
Nonaka myopathy was first described by Nonaka (1981) as an autosomal recessive muscular dystrophy primarily affecting distal muscles, in particular the anterior tibial muscles. Ikeuchi (1997) suggested that Nonaka myopathy and IBM-2 were allelic disorders. Kayashima (2002) performed sequence and haplotype analysis of the GNE gene in 2 sibs with Nonaka myopathy and demonstrated compound heterozygosity for 2 missense variants in both. Their parents and a normal elder brother all carried only one variant. The authors suggested that the main difference between IBM-2 and Nonaka myopathy is the distribution of the muscle weakness; in Nonaka myopathy there is within the first 10 years after onset less sparing of the quadriceps. Tomimitsu (2002) found the same homozygous variant (Val572Leu) in 7/9 Japanese patients with Nonaka myopathy.
Malicdan (2007) generated a mouse models of DMRV/hIBM. Homozygous Gne KO mice expressing the human p.Asp176Val variant (prevalent in Japanese patients) mimiced the clinical, histopathological and biochemical features of DMRV/hIBM in human. Gagiannis (2007) compared the amount of membrane-bound sialic acids of wt mice with those of heterozygous Gne-deficient mice and found an overall organ-specific reduction of 25%. Transferrin-expression was unchanged in heterozygous Gne-deficient mice, but the isoelectric point was shifted towards basic pH indicating a reduced sialyation. The expression of polysialic acids on neural cell adhesion molecule (NCAM) was also reduced.
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