| *603824 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE GLCNE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: GNE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 9p13.3 Genomic coordinates (GRCh37): 9:36,214,437 - 36,277,052 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sialic acid modification of glycoproteins and glycolipids expressed at the cell surface is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. GNE is the rate-limiting enzyme in the sialic acid biosynthetic pathway (Keppler et al., 1999). Hinderlich et al. (1997) reported that biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids, in rat liver is initiated and regulated by a bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; EC 5.1.3.14)/N-acetylmannosamine kinase (ManNAc kinase; EC 2.7.1.60). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Stasche et al. (1997) isolated rat cDNAs encoding the UDP-N-acetylglucosamine 2-epimerase. Secreting organs, such as liver, salivary glands, and intestinal mucosa, showed high UDP-GlcNAc 2-epimerase/ManNAc kinase activity. Keppler et al. (1999) determined that UDP-GlcNAc 2-epimerase activity is rate-limiting for the biosynthesis of sialic acid and is required for sialylation in hematopoietic cells. The activity of the enzyme can be controlled at the transcriptional level and can affect the sialylation and function of specific cell surface molecules expressed on B cells and myeloid cells. In a Genbank submission (AJ238764), these authors reported the sequence of a human UDP-GlcNAc 2-epimerase cDNA. Tomimitsu et al. (2004) identified 2 isoforms of GNE: a longer form, comprising 556 bp, and a shorter form, with exon 4 missing and comprising 403 bp. The shorter isoform was predominantly expressed in skeletal muscle, whereas the longer isoform was predominantly expressed in all other tissues. The shorter isoform was expressed in skeletal muscle of both controls and patients with distal myopathy with rimmed vacuoles (605820), with no difference between the 2 groups. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By analysis of a mouse-human cell hybrid panel, Huizing and Anikster (2000) assigned the gene that is mutant in sialuria to chromosome 9p12-p11. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sialuria Sialuria (269921) is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free NeuAc. Overproduction of NeuAc was believed to result from loss of feedback inhibition of UDP-GlcNAc 2-epimerase by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). To elucidate the molecular mechanism for defective allosteric regulation of UDP-GlcNAc 2-epimerase in this disease, Seppala et al. (1999) cloned and sequenced the human cDNA encoding the epimerase and determined the mutations in 3 sialuria patients. Three heterozygous mutations, arg266 to trp (603824.0001), arg266 to gln (603824.0002), and arg263 to leu (603824.0003), indicated that the allosteric site of the epimerase resides in the region of codons 263 to 266. The absence of any symptoms in the parents of the affected children indicated that the base changes represented new mutations. Parental DNA was not available for direct analysis. The heterozygous nature of the mutant allele in all 3 patients demonstrated dominant inheritance of sialuria, i.e., heterozygosity for a mutation in the allosteric site is sufficient to cause the disorder. In this case, the mutant epimerase activity continues to produce free sialic acid and CMP-Neu5Ac, which inhibits the normal but not the mutant epimerase. With no brake on the rate-limiting step in sialic acid production, intracellular free sialic acid levels increase indefinitely, leading to the clinical and laboratory findings of sialuria. Dominant inheritance has also been reported in the syndrome of hyperinsulinism and hyperammonemia, in which GTP fails to feedback-inhibit glutamate dehydrogenase (138130) because of mutations affecting the enzyme's allosteric site (see 138130.0003). Autosomal Recessive Inclusion Body Myopathy-2 and Nonaka Myopathy Hereditary inclusion body myopathy (IBM) constitutes a unique 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. Autosomal dominant (IBM3; 605637) and autosomal recessive (IBM2; 600737) forms have been described. The autosomal recessive form, first characterized in Jews of Persian descent, is a myopathy that affects mainly leg muscles, but with an unusual distribution that spares the quadriceps, so-called quadriceps-sparing myopathy (QSM). This disorder was subsequently found in other Middle Eastern families, the gene was mapped to 9p13-p12, and in 104 affected persons from 47 Middle Eastern families the same mutation in homozygous state was found in the GNE gene (Eisenberg et al., 2001). Affected individuals in families of other ethnic origins were found to be compound heterozygotes for other distinct mutations in the GNE gene. Eisenberg et al. (2001) urged the study of GNE in Nonaka distal myopathy (605820) with rimmed vacuoles, described in Japanese patients (Nonaka et al., 1981) and found to map to the same region of chromosome 9 (Ikeuchi et al., 1997) as autosomal recessive inclusion body myopathy. Furthermore, Eisenberg et al. (2001) suggested investigating GNE involvement in sporadic inclusion body myositis, which occurs worldwide and is the most common myopathy in individuals aged 50 and older. Kayashima et al. (2002) performed sequence and haplotype analysis of the GNE gene in 2 sibs with Nonaka myopathy and demonstrated compound heterozygosity for 2 missense mutations (603284.0012, 603284.0013) in both. Their parents and a normal elder brother were all carriers for 1 or the other of the mutations. This was the third disorder related to mutations in the GNE gene. 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 observed by Kayashima et al. (2002) in Nonaka myopathy are located in the sugar kinase domain of the gene. Among 33 Japanese patients and 1 patient of German and Irish ancestry with Nonaka myopathy, Nishino et al. (2002) identified homozygous or compound heterozygous mutations in the GNE gene in 27 unrelated patients. An unaffected father of 1 patient had a homozygous mutation that presumably caused disease in other patients. The V572L mutation (603824.0013) accounted for 61% of the abnormal alleles in the study, indicating a high frequency of carriers of this mutation in Japan. The authors noted that the patient of German and Irish ancestry had a compound mutation, although not the V572L mutation, indicating that the disorder is not restricted to Japan. In an American patient with IBM2, Vasconcelos et al. (2002) identified compound heterozygosity for mutations in the GNE gene, expanding the genetic heterogeneity of the disorder. No mutation in the GNE gene was detected in 11 sporadic IBM patients. Tomimitsu et al. (2004) identified mutations in the GNE gene in 20 of 22 patients diagnosed with Nonaka myopathy. Fifteen patients had the V572L mutation, either in the homozygous or compound heterozygous form. The authors also identified 7 novel GNE mutations. One patient carried the met712-to-thr mutation (M712T; 603824.0005), confirming that inclusion body myopathy and Nonaka myopathy are allelic disorders. Kim et al. (2006) performed clinical and genetic analysis of 9 unrelated Korean patients suspected of having Nonaka myopathy and found that 8 of the 9 were homozygous or compound heterozygous for mutations in the GNE gene. The allelic frequencies of the V572L and C13S mutations were 68.8% and 12.5%, respectively. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Schwarzkopf et al. (2002) reported that inactivation of GNE (which is bifunctional and the key enzyme of sialic acid biosynthesis) by gene targeting in mice caused early embryonic lethality, thereby emphasizing the fundamental role of the enzyme and sialylation during development. The need for the enzyme for a defined sialylation process is exemplified by the polysialylation of the neural cell adhesion molecule in embryonic stem cells. Galeano et al. (2007) created knockin mice with the M712T Gne mutation and found that homozygous mutants did not survive beyond postnatal day 3. On postnatal day 2, there was significantly decreased Gne activity in muscle but no myopathic features; rather, the homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy, with segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of podocalyxin (see 602632). With administration of ManNAc, 43% of homozygous mutants survived beyond postnatal day 3, exhibiting improved renal histology, increased sialylation of podocalyxin, and increased Gne expression and activity. Galeano et al. (2007) concluded that M712T Gne-knockin mice provide a novel animal model of hyposialylation-related podocytopathy and segmental splitting of the glomerular basement membrane, demonstrating the significance of sialic acid synthesis in kidney development and function. Malicdan et al. (2007) generated Gne-deficient mice expressing the human D176V-GNE mutation as a mouse model of distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy (DMRV-HIBM). Complete knockout of the Gne gene was embryonic lethal. Mice with the D176V mutation showed marked hyposialylation in serum, muscle, and other organs. Reduction in motor performance in these mice could only be seen from 30 weeks of age. By 32 weeks, myofibers developed beta-amyloid deposition, which preceded rimmed vacuole formation at 42 weeks. The findings also suggested that hyposialylation plays an important role in the pathomechanism of DMRV-HIBM. Malicdan et al. (2009) found that D176V-mutant mice treated orally with sialic acid showed increased survival, increased motor performance, and decreased number of rimmed vacuoles in skeletal muscle compared to untreated mice with the disorder. Prophylactic treatment prevented development of the myopathic phenotype. The findings indicated that hyposialylation is a key factor in the pathomechanism of DMRV-HIBM. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 SIALURIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ARG266TRP [dbSNP:rs121908621] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with sialuria (269921) who was originally described by Wilcken et al. (1987), Seppala et al. (1999) identified a C-to-T transition in the third base of codon 266 of the GNE gene, resulting in an arg266-to-trp substitution. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 SIALURIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ARG266GLN [dbSNP:rs121908622] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with sialuria (269921) who was originally described by Weiss et al. (1989), Seppala et al. (1999) identified a G-to-A transition in the second base of codon 266 of the GNE gene, resulting in an arg266-to-gln substitution. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 SIALURIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ARG263LEU [dbSNP:rs121908623] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with sialuria (269921) who was originally described by Krasnewich et al. (1993), Seppala et al. (1999) identified a G-to-T transversion in the second base of codon 263 of the GNE gene, resulting in an arg263-to-leu substitution. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 SIALURIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ARG266GLN [dbSNP:rs121908622] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Leroy et al. (2001) described a heterozygous arg266-to-gln (R266Q) mutation in the GNE gene in a child and his mother, confirming dominant inheritance of sialuria (269921). In contrast to all 4 of her sisters, who had graduated from various college-level training programs, the mother had completed only grade school and held domestic employment briefly before marriage. She was of normal stature without dysmorphic features. The urinary level of free NeuAc was elevated. The father, who was unrelated to the mother, had normal urinary findings. At 2 months of age the child had frequent opisthotonic posturing and persistent hypotonia. Anemia required transfusion of packed red blood cells. Excessive rhinorrhea and recurrent respiratory infections were present throughout infancy. Impaired hip and knee extensions were noted at age 15 months. The boy remained hypotonic but alert and physically active. Skeletal x-rays at age 10.5 months showed a skeletal age between 3 and 6 months and mildly widened long bone diaphyses and widened metaphyses of some bones of the limbs. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NONAKA MYOPATHY, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, MET712THR [dbSNP:rs28937594] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 47 Middle Eastern Jewish families, Eisenberg et al. (2001) found that affected individuals with quadriceps-sparing inclusion body myopathy-2 (IBM2; 600737) had a 2186T-C transition in exon 12 of the GNE gene, resulting in a met712-to-thr (M712T) amino acid change in the kinase domain of the protein. In 2 second cousins from an Italian family with IBM2, Broccolini et al. (2002) identified compound heterozygosity for mutations in the GNE gene: M712T and a novel mutation (M171V; 603824.0016). The authors noted that it was the first report of the M712T mutation in patients of non-Middle Eastern descent. Argov et al. (2003) identified homozygosity for the M712T mutation in 129 Middle Eastern patients with IBM2 from 55 families. Eleven patients had atypical features: 5 had involvement of the quadriceps muscle, 2 patients did not have distal weakness, 3 patients had facial weakness, and 1 patient had perivascular inflammation. There were 5 unaffected individuals with the homozygous mutation from 5 different IBM2 families, including 2 who were 50 and 68 years old. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. Argov et al. (2003) offered a detailed historical perspective of the different cultures, and concluded that this founder mutation is approximately 1,300 years old and is not limited to those of Jewish descent. In a Japanese patient with Nonaka myopathy (605820), Tomimitsu et al. (2004) identified compound heterozygosity for the M712T mutation and the A631V mutation (603824.0015). The findings indicated that Nonaka myopathy and IBM2 are allelic, if not identical, disorders. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, GLY576GLU [dbSNP:rs121908625] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a Georgia (USA) family, Eisenberg et al. (2001) found that autosomal recessive inclusion body myopathy (600737) was caused by compound heterozygosity for a gly576-to-glu (G576E) mutation and an ala631-to-thr (A631T; 603824.0007) mutation in the GNE gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ALA631THR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 603824.0006 and Eisenberg et al. (2001). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, VAL696MET | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of an Asiatic Indian family with autosomal recessive inclusion body myopathy (600737), Eisenberg et al. (2001) found compound heterozygosity for 2 missense mutations, val696 to met (V696M) and cys303 to ter (C303X; 603824.0009), in the GNE gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, CYS303TER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 603824.0008 and Eisenberg et al. (2001). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ARG246GLN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family from the Bahamas with autosomal recessive inclusion body myopathy (600737), Eisenberg et al. (2001) found compound heterozygosity for 2 missense mutations in the GNE gene: arg246 to gln (R246Q) and asp225 to asn (D225N; 603824.0011). Both mutations were in exon 4 and the amino acid changes involved the epimerase domain of the protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ASP225ASN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 603824.0010 and Eisenberg et al. (2001). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 NONAKA MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ALA460VAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs with distal myopathy with rimmed vacuoles, or Nonaka myopathy (605820), Kayashima et al. (2002) found compound heterozygosity in the GNE gene for a C-to-T transition in exon 8, resulting in an ala460-to-val (A460V) substitution, and a G-to-C transition in exon 10, resulting in a V572L (603824.0013) substitution. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0013 NONAKA MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, VAL572LEU | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 603824.0012 and Kayashima et al. (2002). In 7 of 9 unrelated Japanese patients with Nonaka myopathy (605820), Tomimitsu et al. (2002) identified a homozygous 1765G-C transition in exon 10 of the GNE gene, resulting in a val572-to-leu (V572L) substitution. An eighth patient was a compound heterozygote for V572L and C303V (603824.0014). Arai et al. (2002) identified the V572L mutation in patients with Nonaka myopathy from 6 consanguineous Japanese families. Haplotype analysis indicated a strong founder effect in these pedigrees. Mean age of onset was 23 years, and most cases became nonambulant within 10 years of disease onset. Tomimitsu et al. (2004) identified the V572L mutation in 15 of 22 patients with Nonaka myopathy: 9 were homozygous and 6 were compound heterozygous for V572L and another mutation in the GNE gene. Kim et al. (2006) identified the V572L mutation in 7 of 8 unrelated Korean patients with Nonaka myopathy: 4 were homozygous and 3 were compound heterozygous for V572L and another mutation in the GNE gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0014 NONAKA MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, CYS303VAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with Nonaka myopathy (605820), Tomimitsu et al. (2002) identified 2 nucleotide substitutions in the GNE gene, 958-959TG-GT, resulting in a cys303-to-val (C303V) change. The patient was a compound heterozygote for this mutation and V572L (603824.0013). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0015 NONAKA MYOPATHY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, ALA631VAL [dbSNP:rs62541771] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 1 of 9 unrelated Japanese patients with Nonaka myopathy (605820), Tomimitsu et al. (2002) identified a homozygous 1943C-T transition in exon 11 of the GNE gene, resulting in an ala631-to-val (A631V) substitution. Of the 9 patients, this patient had the latest age of onset, the slowest progression of disease, and was still able to stand 30 years after onset. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0016 INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GNE, MET171VAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 second cousins from an Italian family with IBM2 (600737), Broccolini et al. (2002) identified compound heterozygosity for mutations in the GNE gene: a 562A-to-G transition in exon 3, resulting in a met171-to-val substitution (M171V) and M712T (603824.0005). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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