HGNC Approved Gene Symbol: GLUD2
Cytogenetic location: Xq24 Genomic coordinates (GRCh38): X:121,047,610-121,050,094 (from NCBI)
Glutamate has a metabolic role and also functions as a major excitatory neurotransmitter. Glutamate dehydrogenases (GLUDs; EC 1.4.1.3) catalyze the conversion of glutamate to alpha-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle in mitochondria, and ammonia, which is metabolized via the urea cycle. GLUD2 is a mitochondrial enzyme that plays a major role in the TCA cycle (summary by Li et al., 2016).
Since blindness due to neuroretinal degeneration occurs in some types of multiple system atrophy, Shashidharan et al. (1994) searched for retina-specific GLUD mRNA(s) by screening a retina cDNA library They cloned a novel cDNA encoded by an X-linked intronless gene, designated GLUD2. RT-PCR analysis of human tissues demonstrated that GLUD2 was expressed in human retina, testis, and, at a lower level, brain. In vitro translation of mRNAs derived from GLUD1 (138130) and GLUD2 generated proteins with distinct electrophoretic characteristics. Expression of the GLUD2 gene in human retina was of particular interest in view of the finding that glutamate is an important retinal excitatory transmitter.
Shashidharan et al. (1994) reported that the GLUD2 coding region is intronless.
Wan and Francke (1998) reported that the GLUD2 gene contains 11 exons.
Shashidharan et al. (1994) mapped the GLUD2 gene to the X chromosome by PCR amplification of DNA derived from hamster/human hybrid lines that contained human chromosome 10 or X. Southern blot analysis of the amplified products, using oligonucleotide probes capable of discriminating between the GLUD1 and GLUD2 genes, revealed that the GLUD2 gene is linked to the human X chromosome, whereas the GLUD1 gene is linked to the human chromosome 10. Also, Southern blot analysis of genomic DNA from males and females showed that females possess a double dose of the GLUD2 gene.
Jung et al. (1989) and Anagnou et al. (1993) mapped the GLUD2 gene to Xq. Online information in the dbSTS database was cited by Wan and Francke (1998) as indicating that the GLUD2 gene is located at Xq25. Francke (1998) stated that the GLUD2 gene was indirectly mapped to Xq25 by sequence identity to a radiation hybrid mapped STS.
Shashidharan et al. (1994) expressed a retina cDNA encoding GLUD2 in the baculovirus heterologous system and found that it produced a protein capable of catalyzing oxidative deamination of glutamate. They noted that partial deficiency of glutamate dehydrogenase has been found in patients with various neurodegenerative disorders, and a deficiency has been thought to cause neuroexcitotoxic nerve cell death (Plaitakis et al. (1982, 1984)). The brains of these patients show loss of glutamate receptors and a selective atrophy of regions that receive glutamatergic terminals and are normally rich in glutamate dehydrogenase immunoreactivity. In these regions, the enzyme is localized in astrocytic processes associated with glutamatergic terminals and is thought to be involved in detoxification of transmitter glutamate. Given the extensive nature of the glutamatergic pathways in brain, Shashidharan et al. (1994) suggested that glutamate dehydrogenase might play a role in a number of human neurodegenerations.
Reclassified Variants
The S445A variant in the GLUD2 gene (300144.0001) that was identified as a modifier for Parkinson disease has been reclassified as a polymorphism. Plaitakis et al. (2010) identified a c.1492T-G polymorphism in the GLUD2 gene (S445A; 300144.0001) that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease.
Exclusion Studies
Wan and Francke (1998) examined the GLUD2 gene as the possible site of mutations causing Rett syndrome (RTT; 312750), an X-linked dominant neurodevelopmental disorder lethal in hemizygous males. The intronless gene GLUD2 is involved in the metabolism of glutamate, a neurotransmitter reported to be elevated in the spinal fluid of RTT individuals. No mutations in the GLUD2 gene were found in 22 RTT patients.
Shashidharan et al. (1994) noted that several other functionless intronless genes generated by reverse transcription and insertion into the human genome as retroposons have been identified. Some of these are expressed in neural tissues, encoding for G protein-linked receptors, or in testis, encoding for the metabolic enzymes pyruvate dehydrogenase and phosphoglycerate kinase. In contrast, the GLUD2 intronless gene is expressed in both neural and testicular tissues. The localization of the GLUD2 gene to the X chromosome and of GLUD1 to chromosome 10 represents a reversal of the chromosomal loci of the 2 forms of pyruvate dehydrogenase and phosphoglycerate kinase; the intronless genes of pyruvate dehydrogenase (PDHA2; 179061) and phosphoglycerate kinase (PGK2; 172270) map to autosomal chromosomes, while their intron-containing genes (PDHA1, 300502; PGK1, 311800) map to the X chromosome. Retroposition of the latter 2 genes to autosomal chromosomes may have occurred in order to serve the metabolic needs of sperm cells, only half of which contain an X chromosome.
The enzyme glutamate dehydrogenase is important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission. It exists in housekeeping and brain-specific isotypes encoded by GLUD1 (138130) and GLUD2, respectively. Burki and Kaessmann (2004) showed that GLUD2 originated by retroposition from GLUD1 in the hominoid ancestor less than 23 million years ago. The amino acid changes responsible for the unique brain-specific properties of the enzyme derived from GLUD2 occurred during a period of positive selection after the duplication event. The genes ASPM (605481) and MCPH1 (607117), determinants of brain size, also showed accelerated evolution during that time. Thus higher neuronal activity may have coevolved with greater brain size and other changes. GLUD2 probably contributed to enhanced brain function in humans and apes by permitting higher neurotransmitter flux. In a commentary on the work of Burki and Kaessmann (2004), Varki (2004) discussed the apparent role of the retrotransposed gene duplicate GLUD2, which acquired brain-specific expression and functions affecting the neurotransmitter glutamate.
To elucidate the function of GLUD2 in humans and great apes, Li et al. (2016) developed 2 transgenic mouse lines carrying a 176-kb BAC containing the human GLUD2 gene and its upstream and downstream sequences. Neither transgenic line showed an overt effect of the transgene, and GLUD2 had no effect on glutamate concentration in mouse cortex. The GLUD2 transgene altered gene transcription and the metabolic profile, but only during early postnatal development. Genes related to neural development and transcriptional regulation predominated among those that showed divergent expression between transgenic and wildtype mice. A comparison of humans and macaques, which have only 1 Glud gene, and examination of fetal human cortex data revealed a similar divergence of gene expression that declined steeply with age. Metabolic profiling of transgenic and wildtype mice showed that the GLUD2 transgene affected pathways surrounding the TCA cycle. Li et al. (2016) also detected expression of a long noncoding RNA (lncRNA) originating from the opposite strand and upstream of the GLUD2 transcription start site. They hypothesized that GLUD2 may function during the period of rapid brain growth and enhance lipid biosynthesis in brain of humans and great apes.
This variant, formerly titled PARKINSON DISEASE, AGE OF ONSET, MODIFIER, has been reclassified as a polymorphism. Hamosh (2023) noted that the S445A variant was present in 5,662 of 205,449 alleles, 71 in homozygosity and 2,188 in hemizygosity, with an allele frequency of 0.02756.
Plaitakis et al. (2010) identified a c.1492T-G polymorphism in the GLUD2 gene, resulting in a ser445-to-ala (S445A) substitution in the regulatory domain, that was associated with earlier age of onset in 2 cohorts of patients with Parkinson disease (PD; 168600). Among 584 Greek patients, 1492G hemizygous males developed PD 8 to 13 years earlier than did patients with the T (p = 0.003), the G/T (p less than 0.001), or the T/T (p = 0.01) genotype. Among 224 North American patients, 1492G hemizygotes also developed PD earlier than those with other genotypes, but the mean age differences reached statistical significance only when G hemizygotes were compared to G/T heterozygotes (mean age difference: 13.1 years, p less than 0.05). Gender did not affect the age at development of PD. The frequency of the G allele was rare (3.6% in the Greek and 4.3% in the American populations). In vitro functional expression studies showed that the variant ala445 enzyme had increased basal activity and thermal stability compared to wildtype. The variant protein showed resistance to suppression by GTP, but was sensitive to inhibition by estrogen. The findings suggested an overall gain of function and explained the lack of effect in female heterozygous PD patients. Plaitakis et al. (2010) postulated that increased glutamate oxidation in the brain may increase reactive oxygen species, which would accelerate a degenerative process.
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Burki, F., Kaessmann, H. Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux. Nature Genet. 36: 1061-1063, 2004. [PubMed: 15378063] [Full Text: https://doi.org/10.1038/ng1431]
Francke, U. Personal Communication. Stanford, Ca. 9/22/1998.
Hamosh, A. Personal Communication. Baltimore, Md. 11/15/2023.
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Li, Q., Guo, S., Jiang, X., Bryk, J., Naumann, R., Enard, W., Tomita, M., Sugimoto, M., Khaitovich, P., Paabo, S. Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development. Proc. Nat. Acad. Sci. 113: 5358-5363, 2016. [PubMed: 27118840] [Full Text: https://doi.org/10.1073/pnas.1519261113]
Plaitakis, A., Berl, S., Yahr, M. D. Abnormal glutamate metabolism in an adult-onset degenerative neurological disorder. Science 216: 193-196, 1982. [PubMed: 6121377] [Full Text: https://doi.org/10.1126/science.6121377]
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Plaitakis, A., Latsoudis, H., Kanavouras, K., Ritz, B., Bronstein, J. M., Skoula, I., Mastorodemos, V., Papapetropoulos, S., Borompokas, N., Zaganas, I., Xiromerisiou, G., Hadjigeorgiou, G. M., Spanaki, C. Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset. Europ. J. Hum. Genet. 18: 336-341, 2010. [PubMed: 19826450] [Full Text: https://doi.org/10.1038/ejhg.2009.179]
Shashidharan, P., Michaelidis, T. M., Robakis, N. K., Kresovali, A., Papamatheakis, J., Plaitakis, A. Novel human glutamate dehydrogenase expressed in neural and testicular tissues and encoded by an X-linked intronless gene. J. Biol. Chem. 269: 16971-16976, 1994. [PubMed: 8207021]
Varki, A. How to make an ape brain. (Commentary) Nature Genet. 36: 1034-1036, 2004. [PubMed: 15454937] [Full Text: https://doi.org/10.1038/ng1004-1034]
Wan, M., Francke, U. Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and Rab GDP-dissociation inhibitor (GDI1). Am. J. Med. Genet. 78: 169-172, 1998. [PubMed: 9674910]