Alternative titles; symbols
HGNC Approved Gene Symbol: GLUD1
SNOMEDCT: 718106009;
Cytogenetic location: 10q23.2 Genomic coordinates (GRCh38) : 10:87,050,202-87,094,843 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.2 | Hyperinsulinism-hyperammonemia syndrome | 606762 | Autosomal dominant | 3 |
L-glutamate dehydrogenase (EC 1.4.1.3) has a central role in nitrogen metabolism in plants and animals. Glutamate dehydrogenase is found in all organisms and catalyzes the oxidative deamination of 1-glutamate to 2-oxoglutarate (Smith et al., 2001). Glutamate, the main substrate of GLUD, is present in brain in concentrations higher than in other organs. In nervous tissue, GLUD appears to function in both the synthesis and the catabolism of glutamate and perhaps in ammonia detoxification (Mavrothalassitis et al., 1988).
Hanauer et al. (1985) detected a cDNA clone expressed in skeletal muscle that they concluded is homologous with GLUD because of close similarities of its deduced amino acid sequence to that of the bovine protein. Mavrothalassitis et al. (1988) reported the characterization of 4 human liver cDNA clones encoding the entire sequence of GLUD. Blot-hybridization analysis of genomic DNA suggested that the human enzyme is encoded by a small multigene family. Multiple GLUD-related transcripts were identified in human, monkey, and rabbit tissues. Nakatani et al. (1988) reported the complete sequence of GLUD cDNA.
Son et al. (2013) reported that whereas most cells use GLUD1 to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, pancreatic ductal adenocarcinoma (see 260350) cells rely on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm, where it can be converted into oxaloacetate by aspartate transaminase (GOT1; 138180). Son et al. (2013) found that knockdown of KRAS (190070) in PDAC cells resulted in a marked increase in GLUD1 and a decrease in GOT1 expression at both the transcriptional and the protein levels. Additionally, they showed that expression on GOT1 increased and GLUD1 decreased in an oncogenic KRAS-dependent manner in vivo. Son et al. (2013) concluded that their findings demonstrated that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway.
Spinelli et al. (2017) found that human breast cancer cells primarily assimilate ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enable other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer (see 114480). In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. Spinelli et al. (2017) concluded that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.
By in situ hybridization, Hanauer et al. (1985) mapped the GLUD1 gene to 10q23-q24.
By analysis of somatic cell hybrids and by in situ hybridization, Anagnou et al. (1989) confirmed the assignment of GLUD1 to chromosome 10, but concluded that the precise localization is 10q21.1-q21.2. By in situ hybridization, Jung et al. (1989) mapped the gene to 10q23, and Deloukas et al. (1993) refined the localization to 10q23.3.
Using a RFLP in the study of recombinant inbred strains, Shaughnessy et al. (1989) found that the murine Glud locus cosegregates with Rib1 (180440) and Tcra (see 186880), which are known to be on mouse chromosome 14. By genomic Southern analysis of a panel of Chinese hamster/mouse somatic cell hybrids, Tzimagiorgis et al. (1991) concluded that there are 2 independent mouse GLUD loci, termed Glud and Glud2, which map to chromosome 14 and 7, respectively. By homology, the Glud locus on chromosome 14 is likely to be the functional one. On the other hand, their evidence appeared to indicate that the Glud2 gene on mouse chromosome 7 is not a processed pseudogene. Both chromosome 7 and 14 of the mouse have regions of linkage homology to human 10q.
Pseudogenes
Several GLUD pseudogenes have been identified. Hanauer et al. (1985) and Anagnou et al. (1989) confirmed the presence of a pseudogene, GLUDP1, on Xq26-28. Jung et al. (1989) mapped the GLUDP1 pseudogene to Xq24. Michaelidis et al. (1993) identified 4 presumed truncated pseudogenes, at least 2 of which may have been generated by retrotransposition. Deloukas et al. (1993) concluded that there are 2 GLUD pseudogenes on 10q which are not linked to the functional gene: GLUDP2 at 10q11.2 and GLUDP3 at 10q22.1. Tzimagiorgis et al. (1993) mapped another locus, termed GLUDP5, to 10p11.2. They pointed out that the work of their group (Michaelidis et al., 1993) raised the number of human GLUD loci to 6.
Michaelidis et al. (1993) determined that the GLUD1 gene is about 45 kb long and contains 13 exons.
Hanauer et al. (1985) suggested that the GLUD clones they detected may be useful in study of the postulated relationship of partial glutamate dehydrogenase deficiency and a form of olivopontocerebellar atrophy (OPCA). Plaitakis et al. (1980, 1982, 1984) and Duvoisin et al. (1983) found partial deficiency of GLUD in fibroblasts and leukocytes of some patients with OPCA. Yamaguchi et al. (1982) and Sorbi et al. (1986) found a similar deficiency in platelets of OPCA patients. Barbeau et al. (1980) could find no abnormality of GLUD in 8 patients with a dominant form of OPCA.
In 2 infants with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Stanley et al. (1997) identified heterozygosity for activating mutations in the GLUD1 gene (138130.0001 and 138130.0002).
In a study of 4 sporadic and 2 familial cases, Stanley et al. (1998) identified 5 missense mutations that alter 1 of 4 amino acids between residues 446 and 454 in exons 11 and 12 of the GLUD1 gene (see, e.g., 138130.0003-138130.0005), a region that encodes the allosteric domain. All of these mutations were associated with a diminished inhibitory effect of guanosine triphosphate (GTP) on glutamate dehydrogenase activity.
In an infant with the syndrome of hypoglycemia due to congenital hyperinsulinism combined with persistent unexplained hyperammonemia (606762), Stanley et al. (1997) identified heterozygosity for a C-to-T transition at nucleotide 1519 in the GLUD1 gene, predicted to cause a his454-to-tyr (H454Y) substitution in the mature protein. The patient was a sporadic case. Also see 138130.0002.
In an infant with the syndrome of hypoglycemia due to congenital hyperinsulinism combined with persistent unexplained hyperammonemia (606762), Stanley et al. (1997) identified heterozygosity for a C-to-T transition at nucleotide 1493 in the GLUD1 gene, predicted to cause a ser445-to-leu (S448L) substitution in the mature GDH peptide. Both of the mutations reported by Stanley et al. (1997) (see 138130.0001) affected only 1 of the 2 GDH alleles and were not present in the parents, indicating that the disorder is autosomal dominant.
In 3 unrelated Japanese infants with congenital hyperinsulinism-hyperammonemia, Miki et al. (2000) identified heterozygosity for the S445L mutation in the allosteric domain of the GLUD1 gene.
In affected members of 2 separate families with hyperinsulinemic hypoglycemia and hyperammonemia (606762), one from Canada and the other from Italy, Stanley et al. (1998) identified heterozygosity for a C-to-T transition at nucleotide 1514, resulting in a ser448-to-pro (S448P) substitution. In each family, a mother and child were affected. This mutation results in less severe hypoglycemia than that seen in patients with a sporadic mutation. Basal enzyme activity was 38% of normal.
In family 2 studied by Thornton et al. (1998), Glaser et al. (1998) identified the S448P mutation in the GLUD1 gene.
In 2 unrelated individuals with hyperinsulinism-hyperammonemia syndrome (606762), Stanley et al. (1998) identified heterozygosity for a G-to-A transition at nucleotide 1508 of the GLUD1 gene, resulting in a gly446-to-ser (G446S) substitution at codon 446. This dominant mutation causes severe hypoglycemia and a 2- to 5-fold increase in plasma ammonium concentration due to decreased sensitivity to GTP-induced inhibition, which was demonstrated in the patients' lymphoblasts.
In 2 unrelated individuals with the hyperinsulinism/hyperammonemia syndrome (606762), Stanley et al. (1998) identified heterozygosity for a G-to-A transition at nucleotide 1509 of the GLUD1 gene, resulting in a gly446-to-asp (G446D) substitution. This dominant mutation results in severe hypoglycemia and a 2- to 5-fold increase in plasma ammonium concentration due to decreased sensitivity to GTP-induced inhibition, which was demonstrated in the patients' lymphoblasts.
In a 6-month-old Japanese girl with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Miki et al. (2000) identified heterozygosity for a 1059A-C transversion in exon 7 of the GLUD1 gene, resulting in a glu296-to-ala (E296A) substitution within the catalytic domain.
In a 6-day-old Japanese boy with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Miki et al. (2000) identified heterozygosity for a 966G-A transition in exon 7 of the GLUD1 gene, resulting in an arg265-to-lys (R265K) substitution within the catalytic domain.
In 5 affected members of a 3-generation family with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Santer et al. (2001) identified heterozygosity for an 833C-T transition in exon 6 of the GLUD1 gene, resulting in an arg221-to-cys (R221C) substitution within the catalytic domain.
In 9 affected members of 6 unrelated families with hyperinsulinemic hypoglycemia and hyperammonemia (606762), Santer et al. (2001) identified heterozygosity for a 978G-A transition in exon 7 of the GLUD1 gene, resulting in an arg269-to-his (R269H) substitution within the catalytic domain.
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Shaughnessy, J., Jr., Mock, B., Duncan, R., Potter, M., Banner, C. A restriction fragment length polymorphism at murine Glud locus cosegregates with Rib-1, Es-10, and Tcra on chromosome 14. Nucleic Acids Res. 17: 2881 only, 1989. [PubMed: 2566156] [Full Text: https://doi.org/10.1093/nar/17.7.2881]
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Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., Perera, R. M., Ferrone, C. R., Mullarky, E., Shyh-Chang, N., Kang, Y., Fleming, J. B., Bardeesy, N., Asara, J. M., Haigis, M. C., DePinho, R. A., Cantley, L. C., Kimmelman, A. C. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496: 101-105, 2013. Note: Erratum: Nature 499: 504 only, 2013. [PubMed: 23535601] [Full Text: https://doi.org/10.1038/nature12040]
Sorbi, S., Tonini, S., Giannini, E., Piacentini, S., Marini, P., Amaducci, L. Abnormal platelet glutamate dehydrogenase activity and activation in dominant and nondominant olivopontocerebellar atrophy. Ann. Neurol. 19: 239-245, 1986. [PubMed: 3963768] [Full Text: https://doi.org/10.1002/ana.410190304]
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