Alternative titles; symbols
HGNC Approved Gene Symbol: GNE
SNOMEDCT: 238051008, 702382000;
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:36,214,441-36,276,978 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Nonaka myopathy | 605820 | Autosomal recessive | 3 |
| Sialuria | 269921 | Autosomal dominant | 3 | |
| Thrombocytopenia 12 with or without myopathy | 620757 | Autosomal recessive | 3 |
The GNE gene encodes UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase; EC 5.1.3.14)/N-acetylmannosamine kinase (ManNAc kinase; EC 2.7.1.60), a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids (Hinderlich et al., 1997).
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).
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 Nonaka myopathy (NM; 605820), with no difference between the 2 groups.
The GNE gene is highly expressed in hematopoietic progenitor cells, including platelets (summary by Futterer et al., 2018).
Huizing et al. (2014) stated that the GNE gene contains 13 exons.
Huizing et al. (2014) noted that 8 GNE splice variants had been identified to that time. They noted that for mutation annotation purposes, 2 major transcripts are relevant: variant 2 (the originally described GNE protein), which encodes 722 amino acids, and variant 1 (the longest mRNA transcript), which encodes 753 amino acids.
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.
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).
Arnadottir et al. (2022) identified a homozygous missense mutation (c.1132G-T, NM_005476.5, D378Y) in the GNE gene in an Icelandic infant who died shortly after birth with acidosis, a ventricular septal defect, micro-Ebstein anomaly (see 224700), and polysplenia. The mutation was found by analyzing whole-genome data from a large cohort of over 153,054 adult Icelandic individuals for a deficit of carriers of homozygous missense variants in different genes. The affected individual was then identified from a clinical cohort of Icelandic patients with various disorders who had undergone whole-genome sequencing. The authors noted that homozygosity for the D378Y mutation had not previously been reported. Among 9 Icelandic couples in which both healthy individuals carried a heterozygous D378Y mutation, 6 women (66.7%) had a medical history of miscarriage, which is significantly higher than the 26.7% rate of miscarriage among Icelandic women in the general population (OR of 6.0). Arnadottir et al. (2022) suggested that homozygosity for the D378Y mutation causes a reduction in sialic acid production that is below the critical sialylation threshold necessary for early human development.
Nonaka Myopathy
Nonaka myopathy (NM; 605820) affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. The disorder was first described in Japanese by Nonaka et al. (1981), and designated distal myopathy with rimmed vacuoles (DMRV), and later in Jews of Persian descent by Argov and Yarom (1984), and designated hereditary inclusion body myopathy (HIBM). Originally thought to be separate disorders, they were both found to be caused by mutation in the GNE gene and were eventually determined to be the same (Nishino et al., 2002; Tomimitsu et al., 2002).
In affected individuals with NM from 47 Middle Eastern families, Eisenberg et al. (2001) identified the same homozygous missense mutation in the GNE gene (M712T; 603824.0005). In affected individuals in families of other ethnic origins, they identified distinct compound heterozygous mutations in GNE (603824.0006-603824.0011).
Kayashima et al. (2002) performed sequence and haplotype analysis of the GNE gene in 2 sibs with NM 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 one or the other of the mutations.
Among 33 Japanese patients and 1 patient of German and Irish ancestry with NM, 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 NM, Vasconcelos et al. (2002) identified compound heterozygous mutations in the GNE gene (603824.0015; 603824.0017). No mutation in the GNE gene was detected in 11 sporadic patients with inclusion body myopathy.
Tomimitsu et al. (2004) identified mutations in the GNE gene in 20 of 22 patients with Nonaka myopathy. Fifteen patients had the V572L mutation, either in homozygous or compound heterozygous state. The authors also identified 7 novel GNE mutations. One patient carried the met712-to-thr mutation (M712T; 603824.0005), confirming that hereditary inclusion body myopathy and Nonaka myopathy are allelic or identical 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.
Thrombocytopenia 12 With or Without Myopathy
In 2 adult Japanese sibs with congenital thrombocytopenia-12 with myopathy (THC12; 620757), Izumi et al. (2014) identified compound heterozygous missense mutations in the GNE gene: V603L (603824.0013) and G739S (603824.0018). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The authors noted that the V603L mutation in the GNE gene is the most common among the Japanese population.
In 9 patients from 3 unrelated families with THC12 without myopathy, Revel-Vilk et al. (2018) identified homozygous or compound heterozygous mutations in the GNE gene (see, e.g., L517P; 603824.0019). The patients ranged from 6 to 42 years of age. Functional studies of the variants were not performed.
In 2 unrelated children, each born of consanguineous parents, with THC12 without myopathy, Bottega et al. (2022) identified homozygous mutations in the GNE gene (V516R, 603824.0020 and T575R, 603824.0021). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families and were not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed reduced GNE protein expression. Patient serum transferrin glycoforms showed higher levels of asialo-, disialo-, and trisialo- forms and decreased tertrasialoforms compared to controls. These findings suggested that the mutations resulted in a partial loss of GNE function.
In a 13-year-old boy, born of unrelated parents, with THC12 without myopathy, Huang et al. (2024) identified compound heterozygous missense mutations in the GNE gene (C594Y, 603824.0022 and P735R, 603824.0023). The mutations, which were found by targeted exome sequencing and confirmed by Sanger sequencing, both occurred in the C-terminal ManNAc kinase domain.
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.
Huang et al. (2024) found that mice homozygous for the GNE P735R mutation developed fatal cerebral hemorrhage at the early embryonic stage. Histologic studies of brains from mutant mice showed defective angiogenesis with fewer and distended vascular sprouts and abnormal megakaryocyte accumulation in the perineural vascular plexus, even though circulating megakaryocytes were decreased. Western blot analysis showed decreased levels of the P735R protein, and there was defective sialic acid biosynthesis and impaired protein sialylation compared to controls. RNA-seq studies of brain tissue from the mutant mice showed abnormal expression of genes related to angiogenesis, These findings suggested a role for Gne in angiogenesis during embryonic development.
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 (R266W) substitution.
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 (R266Q) substitution.
In a boy (patient 1) with sialuria, Leroy et al. (2001) described heterozygosity for a c.848G-A transition (c.848G-A, NM_005476) in the GNE gene resulting in the R266Q mutation. His mother (patient 2) was found to carry the same heterozygous mutation, confirming dominant inheritance of the disorder. 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.
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 (R263L) substitution.
Huizing et al. (2014) noted the identification of an additional N-terminal 31 amino acids encoded by the longest GNE transcript (NM_001128227); thus, they renumbered the MET712THR mutation as MET743THR (M743T).
In 47 Middle Eastern Jewish families, Eisenberg et al. (2001) found that affected individuals with Nonaka myopathy (NM; 605820), which the authors called hereditary inclusion body myopathy (HIBM), had a c.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 diagnosed with HIBM, 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 diagnosed with HIBM 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 HIBM 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, Tomimitsu et al. (2004) identified compound heterozygosity for the M712T mutation and the A631V mutation (603824.0015). The findings indicated that Nonaka myopathy and what was previously called hereditary inclusion body myopathy are identical disorders.
In a Georgia (USA) family, Eisenberg et al. (2001) found that Nonaka myopathy (NM; 605820), which the authors called hereditary inclusion body myopathy, was caused by compound heterozygosity for 2 mutations in the GNE gene: a gly576-to-glu (G576E) substitution and an ala631-to-thr (A631T; 603824.0007) substitution.
For discussion of the ala631-to-thr (A631T) mutation in the GNE gene that was found in compound heterozygous state in a patient with Nonaka syndrome (NM; 605820) by Eisenberg et al. (2001), see 603824.0006.
Huizing et al. (2014) noted the identification of an additional N-terminal 31 amino acids encoded by the longest GNE transcript (NM_001128227); thus, they renumbered the VAL696MET mutation as VAL727MET (V727M).
In an Asiatic Indian family, Eisenberg et al. (2001) found that Nonanka myopathy (NM; 605820), which the authors called hereditary inclusion body myopathy, was caused by compound heterozygous mutations in the GNE gene: val696 to met (V696M) and cys303 to ter (C303X; 603824.0009).
Lek et al. (2016) questioned the pathogenicity of this variant because it has a high allele frequency (0.0141) in the South Asian population in the ExAC database.
For discussion of the cys303-to-ter (C303X) mutation in the GNE gene that was found in compound heterozygous state in an Asiatic Indian family with Nonaka myopathy (NM; 605820) by Eisenberg et al. (2001), see 603824.0008.
In a family from the Bahamas, Eisenberg et al. (2001) found that Nonaka myopathy (NM; 605820), which the authors called hereditary inclusion body myopathy, was caused by compound heterozygous 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.
For discussion of the asp225-to-asn (D225N) mutation in the GNE gene that was found in compound heterozygous state in patients with Nonaka myopathy (NM; 605820) by Eisenberg et al. (2001), see 603824.0010.
In 2 sibs with distal myopathy with rimmed vacuoles, or Nonaka myopathy (NM; 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.
Huizing et al. (2014) noted the identification of an additional N-terminal 31 amino acids encoded by the longest GNE transcript (NM_001128227); thus, they renumbered the VAL572LEU mutation as VAL603LEU (V603L).
Nonaka Myopathy
For discussion of the val572-to-leu (V572L) mutation in the GNE gene that was found in compound heterozygous state in patients with Nonaka myopathy (NM; 605820) by Kayashima et al. (2002), see 603824.0012.
In 7 of 9 unrelated Japanese patients with Nonaka myopathy, Tomimitsu et al. (2002) identified a homozygous c.1765G-C transversion 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.
Thrombocytopenia 12 With Myopathy
In 2 Japanese sibs with congenital thrombocytopenia-12 with myopathy (THC12; 620757), Izumi et al. (2014) identified compound heterozygous missense mutations in the GNE gene: V603L and G739S (603824.0018). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The authors noted that the V603L mutation in the GNE gene is the most common among the Japanese population.
In a patient with Nonaka myopathy (NM; 605820), Tomimitsu et al. (2002) identified 2 nucleotide substitutions in the GNE gene, c.958_959TG-GT, resulting in a cys303-to-val (C303V) change. The patient was compound heterozygous for this mutation and V572L (603824.0013).
In 1 of 9 unrelated Japanese patients with Nonaka myopathy (NM; 605820), Tomimitsu et al. (2002) identified a homozygous c.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.
In affected members of an American family with NM, Vasconcelos et al. (2002) identified compound heterozygous mutations in the GNE gene: A631V and a c.698T-C transition in exon 4 resulting in a val216-to-ala (V216A; 603824.0017) substitution. Vasconcelos et al. (2002) called the disorder quadriceps-sparing inclusion body myopathy.
In 2 second cousins from an Italian family with Nonaka myopathy (NM; 605820), Broccolini et al. (2002) identified compound heterozygosity for mutations in the GNE gene: a c.562A-to-G transition in exon 3, resulting in a met171-to-val substitution (M171V) and M712T (603824.0005). The authors called the disorder hereditary inclusion body myopathy.
For discussion of the c.698T-C transition in the GNE gene, resulting in a val216-to-ala (V216A) substitution, that was found in compound heterozygous state in affected members of an American family with Nonaka myopathy (NM; 605820) by Vasconcelos et al. (2002), see 603824.0015.
In 2 Japanese sibs with congenital thrombocytopenia-12 with myopathy (THC12; 620757), Izumi et al. (2014) identified compound heterozygous missense mutations in the GNE gene: a c.2215G-A transition (c.2215G-A, NM_001128227) resulting in a gly739-to-ser (G739S) substitution, and V603L (603824.0013). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Exome sequencing also identified biallelic mutations in 2 other genes that segregated with THC12 in this family: a homozygous c.627_628insCCG (Ser209delinsSP) in the CPEB2 gene (610605) and compound heterozygosity for T907M and S1159L in the FLNB gene (603381). Functional studies of the variants and studies of patient cells were not performed.
In 3 sibs, ranging from 6 to 14 years of age and born of consanguineous Palestinian Arab parents (family 2) with congenital thrombocytopenia-12 (THC12; 620757) without myopathy, Revel-Vilk et al. (2018) identified a homozygous T-to-C transition in exon 9 of the GNE gene, resulting in a leu517-to-pro (L517P) substitution at a conserved residue in the kinase domain. Functional studies of the variant were not performed. Revel-Vilk et al. (2018) referred to the mutation as c.1457T-C, L486P in the text of the report, and as L517P in Supplementary Figure 2.
In an 18-month-old boy (P1), born of consanguineous Egyptian parents, with thrombocytopenia-12 without myopathy (THC12; 620757), Bottega et al. (2022) identified a homozygous c.1546_1547delinsAG mutation (c.1546_1547delinsAG, NM_001128227.3) in the GNE gene, resulting in a val516-to-arg (V516R) substitution at a conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed reduced GNE protein expression (39% of normal). Serum transferrin glycoforms showed a higher level of asialo-, disialo-, and trisialo- forms and a decrease in tetrasialoforms compared to controls. These findings suggested that the mutation resulted in a partial loss of GNE function.
In a 4-year-old boy (P2), born of consanguineous Moroccan parents, with thrombocytopenia-12 without myopathy (THC12; 620757), Bottega et al. (2022) identified a homozygous c.1724C-G transversion (c.1724C-G, NM_001128227.3) in the GNE gene, resulting in a thr575-to-arg (T575R) substitution at a conserved residue in the kinase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family, and was not found in the gnomAD database. Western blot analysis of patient lymphoblasts showed reduced GNE protein expression (79% of normal). Serum transferrin glycoforms showed a higher level of asialo-, disialo-, and trisialo- forms and a decrease in tetrasialoforms compared to controls. These findings suggested that the mutation resulted in a partial loss of GNE function.
In a 13-year-old boy, born of unrelated parents, with congenital thrombocytopenia-12 without myopathy (THC12; 620757), Huang et al. (2024) identified compound heterozygous missense mutations in the GNE gene: a c.1781G-A transition (c.1781G-A, NM_001128227.3) in exon 10, resulting in a cys594-to-tyr (C594Y) substitution, and a c.2204C-G transversion in exon 12, resulting in a pro735-to-arg substitution (P735R; 603824.0023). The mutations, which were found by targeted exome sequencing and confirmed by Sanger sequencing, both occurred in the C-terminal ManNAc kinase domain. The C594Y mutation was present in the unaffected father, but DNA from the unaffected mother was not available.
For discussion of the c.2204C-G transversion (c.2204C-G, NM_001128227.3) in exon 12 of the GNE gene, resulting in a pro735-to-arg (P735R) substitution, that was found in compound heterozygous state in a patient with congenital thrombocytopenia-12 without myopathy (THC12; 620757) by Huang et al. (2024), see 603824.0022.
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. 52: 516-519, 2002. [PubMed: 12325084] [Full Text: https://doi.org/10.1002/ana.10341]
Argov, A., Yarom, R. 'Rimmed vacuole myopathy' sparing the quadriceps: a unique disorder in Iranian Jews. J. Neurol. Sci. 64: 33-43, 1984. [PubMed: 6737002] [Full Text: https://doi.org/10.1016/0022-510x(84)90053-4]
Argov, Z., Eisenberg, I., Grabov-Nardini, G., Sadeh, M., Wirguin, I., Soffer, D., Mitrani-Rosenbaum, S. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60: 1519-1523, 2003. [PubMed: 12743242] [Full Text: https://doi.org/10.1212/01.wnl.0000061617.71839.42]
Arnadottir, G. A., Oddsson, A., Jensson, B. L., Gisladottir, S., Simon, M. T., Arnthorsson, A. O., Katrinardottir, H., Fridriksdottir, R., Ivarsdottir, E. V., Jonasdottir, A., Jonasdottir, A., Barrick, R., 21 others. Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene. Nature Commun. 13: 705, 2022. [PubMed: 35121750] [Full Text: https://doi.org/10.1038/s41467-022-28330-8]
Bottega, R., Marzollo, A., Marinoni, M., Athanasakis, E., Persico, I., Bianco, A. M., Faleschini, M., Valencic, E., Simoncini, D., Rossini, L., Corsolini, F., La Bianca, M., and 13 others. GNE-related thrombocytopenia: evidence for a mutational hotspot in the ADP/substrate domain of the GNE bifunctional enzyme. Haematologica 107: 750-754, 2022. [PubMed: 34788986] [Full Text: https://doi.org/10.3324/haematol.2021.279689]
Broccolini, A., Pescatori, M., D'Amico, A., Sabino, A., Silvestri, G., Ricci, E., Servidei, S., Tonali, P. A., Mirabella, M. An Italian family with autosomal recessive inclusion-body myopathy and mutations in the GNE gene. Neurology 59: 1808-1809, 2002. [PubMed: 12473780] [Full Text: https://doi.org/10.1212/01.wnl.0000031808.04545.e0]
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, W. G., Baumbach, L., Lancet, D., Ben Asher, E., Beckmann, J. S., Argov, Z., Mitrani-Rosenbaum, S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nature Genet. 29: 83-87, 2001. [PubMed: 11528398] [Full Text: https://doi.org/10.1038/ng718]
Futterer, J., Dalby, A., Lowe, G. C., Johnson, B., Simpson, M. A., Motwani, J., Williams, M., Watson, S. P., Morgan, N. V. Mutation in GNE is associated with severe congenital thrombocytopenia. Blood 132: 1855-1858, 2018. [PubMed: 29941673] [Full Text: https://doi.org/10.1182/blood-2018-04-847798]
Galeano, B., Klootwijk, R., Manoli, I., Sun, M., Ciccone, C., Darvish, D., Starost, M. F., Zerfas, P. M., Hoffmann, V. J., Hoogstraten-Miller, S., Krasnewich, D. M., Gahl, W. A., Huizing, M. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J. Clin. Invest. 117: 1585-1594, 2007. [PubMed: 17549255] [Full Text: https://doi.org/10.1172/JCI30954]
Hinderlich, S., Stasche, R., Zeitler, R., Reutter, W. A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver: purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem. 272: 24313-24318, 1997. [PubMed: 9305887] [Full Text: https://doi.org/10.1074/jbc.272.39.24313]
Huang, L., Kondo, Y., Cao, L., Han, J., Li, T., Zuo, B., Yang, F., Li, Y., Ma, Z., Bai, X., Jiang, M., Ruan, C., Xia, L. Novel GNE missense variants impair de novo sialylation and cause defective angiogenesis in the developing brain in mice. Blood Adv. 8: 991-1001, 2024. [PubMed: 38237079] [Full Text: https://doi.org/10.1182/bloodadvances.2023011490]
Huizing, M., Anikster, Y. Personal Communication. Bethesda, Md. 1/10/2000.
Huizing, M., Carrillo-Carrasco, N., Malicdan, M. C. V., Noguchi, S., Gahl, W. A., Mitrani-Rosenbaum, S., Argov, Z., Nishino, I. GNE myopathy: new name and new mutation nomenclature. Neuromusc. Disord. 24: 387-389, 2014. [PubMed: 24685570] [Full Text: https://doi.org/10.1016/j.nmd.2014.03.004]
Izumi, R., Niihori, T., Suzuki, N., Sasahara, Y., Rikiishi, T., Nishiyama, A., Nishiyama, S., Endo, K., Kato, M., Warita, H., Konno, H., Takahashi, T., Tateyama, M., Nagashima, T., Funayama, R., Nakayama, K., Kure, S., Matsubara, Y., Aoki, Y., Aoki, M. GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. Neuromusc. Disord. 24: 1068-1072, 2014. [PubMed: 25257349] [Full Text: https://doi.org/10.1016/j.nmd.2014.07.008]
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. 47: 77-79, 2002. [PubMed: 11916006] [Full Text: https://doi.org/10.1007/s100380200004]
Keppler, O. T., Hinderlich, S., Langner, J., Schwartz-Albiez, R., Reutter, W., Pawlita, M. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 284: 1372-1376, 1999. [PubMed: 10334995] [Full Text: https://doi.org/10.1126/science.284.5418.1372]
Kim, B. J., Ki, C.-S., Kim, J.-W., Sung, D. H., Choi, Y.-C., Kim, S. H. Mutation analysis of the GNE gene in Korean patients with distal myopathy with rimmed vacuoles. J. Hum. Genet. 51: 137-140, 2006. Note: Erratum: J. Hum. Genet. 51: 840 only, 2006. [PubMed: 16372135] [Full Text: https://doi.org/10.1007/s10038-005-0338-5]
Krasnewich, D. M., Tietze, F., Krause, W., Pretzlaff, R., Wenger, D. A., Diwadkar, V., Gahl, W. A. Clinical and biochemical studies in an American child with sialuria. Biochem. Med. Metab. Biol. 49: 90-96, 1993. [PubMed: 8439453] [Full Text: https://doi.org/10.1006/bmmb.1993.1010]
Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536: 285-291, 2016. [PubMed: 27535533] [Full Text: https://doi.org/10.1038/nature19057]
Leroy, J. G., Seppala, R., Huizing, M., Dacremont, G., De Simpel, H., Van Coster, R. N., Orvisky, E., Krasnewich, D. M., Gahl, W. A. Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am. J. Hum. Genet. 68: 1419-1427, 2001. [PubMed: 11326336] [Full Text: https://doi.org/10.1086/320598]
Malicdan, M. C. V., Noguchi, S., Hayashi, Y. K., Nonaka, I., Nishino, I. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nature Med. 15: 690-695, 2009. [PubMed: 19448634] [Full Text: https://doi.org/10.1038/nm.1956]
Malicdan, M. C. V., Noguchi, S., Nonaka, I., Hayashi, Y. K., Nishino, I. A Gne knockout mouse expressing human GNE D176V mutation develops features similar to distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy. Hum. Molec. Genet. 16: 2669-2682, 2007. [PubMed: 17704511] [Full Text: https://doi.org/10.1093/hmg/ddm220]
Nishino, I., Noguchi, S., Murayama, K., Driss, A., Sugie, K., Oya, Y., Nagata, T., Chida, K., Takahashi, T., Takusa, Y., Ohi, T., Nishiyama, J., Sunohara, N., Ciafaloni, E., Kawai, M., Aoki, M., Nonaka, I. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59: 1689-1693, 2002. [PubMed: 12473753] [Full Text: https://doi.org/10.1212/01.wnl.0000041631.28557.c6]
Nonaka, I., Sunohara, N., Ishiura, S., Satoyoshi, E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J. Neurol. Sci. 51: 141-155, 1981. [PubMed: 7252518] [Full Text: https://doi.org/10.1016/0022-510x(81)90067-8]
Revel-Vilk, S., Shai, E., Turro, E., Jahshan, N., Hi-Am, E., Spectre, G., Daum, H., Kalish, Y., Althaus, K., Greinacher, A., Kaplinsky, C., Izraeli, S., Mapeta, R., Deevi, S. V. V., Jarocha, D., Ouwehand, W. H., Downes, K., Poncz, M., Varon, D., Lambert, M. P. GNE variants causing autosomal recessive macrothrombocytopenia without associated muscle wasting. Blood 132: 1851-1854, 2018. [PubMed: 30171045] [Full Text: https://doi.org/10.1182/blood-2018-04-845545]
Schwarzkopf, M., Knobeloch, K.-P., Rohde, E., Hinderlich, S., Wiechens, N., Lucka, L., Horak, I., Reutter, W., Horstkorte, R. Sialylation is essential for early development in mice. Proc. Nat. Acad. Sci. 99: 5267-5270, 2002. [PubMed: 11929971] [Full Text: https://doi.org/10.1073/pnas.072066199]
Seppala, R., Lehto, V.-P., Gahl, W. A. 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. 64: 1563-1569, 1999. [PubMed: 10330343] [Full Text: https://doi.org/10.1086/302411]
Stasche, R., Hinderlich, S., Weise, C., Effertz, K., Lucka, L., Moormann, P., Reutter, W. A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver: molecular cloning and functional expression of UDP-N-acetyl-glucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem. 272: 24319-24324, 1997. [PubMed: 9305888] [Full Text: https://doi.org/10.1074/jbc.272.39.24319]
Tomimitsu, H., Ishikawa, K., Shimizu, J., Ohkoshi, N., Kanazawa, I., Mizusawa, H. Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene. Neurology 59: 451-454, 2002. [PubMed: 12177386] [Full Text: https://doi.org/10.1212/wnl.59.3.451]
Tomimitsu, H., Shimizu, J., Ishikawa, K., Ohkoshi, N., Kanazawa, I., Mizusawa, H. Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. Neurology 62: 1607-1610, 2004. [PubMed: 15136692] [Full Text: https://doi.org/10.1212/01.wnl.0000123115.23652.6c]
Vasconcelos, O. M., Raju, R., Dalakas, M. C. GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM. Neurology 59: 1776-1779, 2002. [PubMed: 12473769] [Full Text: https://doi.org/10.1212/01.wnl.0000039780.13681.ad]
Weiss, P., Tietze, F., Gahl, W. A., Seppala, R., Ashwell, G. Identification of the metabolic defect in sialuria. J. Biol. Chem. 264: 17635-17636, 1989. [PubMed: 2808337]
Wilcken, B., Don, N., Greenaway, R., Hammond, J., Sosula, L. Sialuria: a second case. J. Inherit. Metab. Dis. 10: 97-102, 1987. [PubMed: 2443758] [Full Text: https://doi.org/10.1007/BF01800030]