Alternative titles; symbols
HGNC Approved Gene Symbol: GLS
SNOMEDCT: 1222662000;
Cytogenetic location: 2q32.2 Genomic coordinates (GRCh38): 2:190,880,821-190,965,552 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q32.2 | ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development | 618339 | Autosomal dominant | 3 |
| Developmental and epileptic encephalopathy 71 | 618328 | Autosomal recessive | 3 | |
| Global developmental delay, progressive ataxia, and elevated glutamine | 618412 | Autosomal recessive | 3 |
Sahai (1983) demonstrated phosphate-activated glutaminase (EC 3.5.1.2) in human platelets. It is the major enzyme yielding glutamate from glutamine. Significance of the enzyme derives from its possible implication in behavior disturbances in which glutamate acts as a neurotransmitter (Prusiner, 1981). High heritability of platelet glutaminase was indicated by studies of Sahai and Vogel (1983) who found an intraclass correlation coefficient of 0.96 for monozygotic twins and 0.53 for dizygotic twins.
By screening for cDNAs encoding large proteins in brain, Nagase et al. (1998) identified a cDNA encoding GLS, which they termed KIAA0838. The deduced 669-amino acid protein is predicted to be 94% identical to the rat kidney glutaminase. RT-PCR analysis detected ubiquitous expression, with highest levels in brain and kidney.
By screening a colon carcinoma cDNA library with a rat kidney Gls probe, followed by 5-prime and 3-prime RACE, Elgadi et al. (1999) isolated cDNAs encoding 3 isoforms of GLS, which they designated KGA, GAM, and GAC. KGA is the 669-amino acid kidney isoform. GAC is a 598-amino acid protein which differs from KGA at the C terminus. GAM is a 169-amino acid protein, which is identical to GAC up to amino acid 161 and contains a unique 8-amino acid C terminus. Northern blot analysis revealed expression of 4.8- and 3.5-kb KGA transcripts in kidney; the 4.8-kb transcript in brain and, weakly, in heart; and a 3.4-kb transcript in pancreas. A 4.8-kb GAC-specific transcript is expressed in heart and pancreas, and at lower levels in placenta, kidney, and lung. GAC is also the predominant isoform expressed in a breast cancer cell line with high glutamine consumption. A 2.6-kb GAM-specific transcript is expressed only in heart and skeletal muscle.
Altered glucose metabolism in cancer cells is termed the Warburg effect, which describes the propensity of most cancer cells to take up glucose avidly and convert it primarily to lactate, despite available oxygen. Cancer cells also depend on continued mitochondrial function for metabolism, specifically glutaminolysis that catabolizes glutamine to generate ATP and lactate. Glutamine, which is highly transported into proliferating cells, is a major source of energy and nitrogen for biosynthesis, and a carbon substrate for anabolic processes in cancer cells. Gao et al. (2009) reported that the c-Myc (190080) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR23a (607962) and miR23b (610723), resulting in greater expression of their target protein, mitochondrial glutaminase (GLS), in human P-493 B lymphoma cells and PC3 prostate cancer cells. This effect leads to upregulation of glutamine catabolism. Glutaminase converts glutamine to glutamate, which is further catabolized through the tricarboxylic acid cycle for the production of ATP or serves as substrate for glutathione synthesis. Gao et al. (2009) concluded that the unique means by which Myc regulates glutaminase uncovers a previously unsuspected link between Myc regulation of microRNAs, glutamine metabolism, and energy and reactive oxygen species homeostasis.
By genomic DNA sequence analysis, Elgadi et al. (1999) proposed that all 3 GLS isoforms are derived from a single gene through alternative splicing.
Mock et al. (1989) used a rat cDNA clone encoding a portion of phosphate-activated glutaminase to identify DNA RFLPs in sets of somatic cell hybrids and between wild-derived and inbred strains of mice. Segregation of rat and mouse chromosomes among somatic cell hybrids indicated assignment to rat chromosome 9 and mouse chromosome 1. Analysis of chromosome 1 alleles with several genes in an interspecific mouse cross indicated more precisely the location of Gls on mouse chromosome 1. Human-hamster somatic cell hybrids were also examined for RFLPs, and 4 human EcoRI restriction fragments were found to hybridize with the rat glutaminase probe. Two of these restriction fragments cosegregated and could be mapped to human 2q near IDH1 (147700) in a region that shows homology (i.e., conserved synteny) with mouse chromosome 1 and rat chromosome 9. By in situ hybridization, Modi et al. (1991) assigned the GLS gene to 2q32-q34. By radiation hybrid analysis, Nagase et al. (1998) mapped the GLS gene to chromosome 2.
Lynch et al. (2018) reported 2 brothers from a consanguineous Turkish family who developed childhood-onset (age 7 years) spastic ataxia with optic atrophy and loss of motor and language skills. MRI in both boys demonstrated mild cerebellar atrophy with preservation of the cerebral and brainstem volumes and normal white matter signal. Nerve conduction studies and muscle biopsies were normal. Through a combination of homozygosity mapping and whole-genome sequencing, Lynch et al. (2018) identified a homozygous copy number variant involving exon 1 of the GLS gene. The duplication led to complete knockout of GLS expression, confirmed in whole cell lysates extracted from fibroblast cell lines of the patients, their parents, and 2 unrelated controls. Plasma glutamine levels were not reported. The duplication was approximately 8 kb and spanned exon 1 and part of the upstream region of GLS and part of intron 1 of the GLS gene. The breakpoint occurred between between a highly homologous region of intron 1-2 (chr 2:191,750,021) and the 5-prime untranslated region (chr2:191,742,079).
Developmental and Epileptic Encephalopathy 71
In 3 patients from 2 unrelated families with lethal developmental and epileptic encephalopathy-71 (DEE71; 618328), Rumping et al. (2019) identified homozygous or compound heterozygous mutations in the GLS gene (138280.0001-138280.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutations were predicted to result in a loss of function, and newborn Guthrie cards from affected individuals in 1 family (family 2) showed significantly increased glutamine, consistent with a loss of GLS function.
Infantile Cataract, Skin Abnormalities, Glutamate Excess, and Impaired Intellectual Development
In a girl with infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, Rumping et al. (2019) identified a heterozygous de novo missense mutation in the GLS gene (138280.0004).
Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine
In 3 unrelated probands with impaired intellectual development, progressive ataxia, and elevated plasma glutamine (GDPAG; 618412), van Kuilenburg et al. (2019) identified a novel trinucleotide (GCA) repeat expansion (138280.0005) in the 5-prime untranslated region (UTR) of the GLS gene. The repeat expansion was found in homozygosity in 1 patient and occurred in compound heterozygosity with a missense mutation (138280.0006) and a 1-basepair duplication (138280.0007), respectively, in the other 2 patients. The expansion resulted in reduced expression and glutaminase deficiency. Knockdown of 1 or both zebrafish orthologs glsa and glsl produced smaller body size, curved body, and cardiac edema of varying severity.
In an infant, born of consanguineous parents (family 1), with lethal developmental and epileptic encephalopathy-71 (DEE71; 618328), Rumping et al. (2019) identified a homozygous 1-bp duplication (c.695dup, NM_001256310.1) in the GLS gene, predicted to result in a frameshift and premature termination (Asp232GlufsTer2). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The patient developed respiratory insufficiency and refractory seizures shortly after birth. EEG showed a burst-suppression pattern. The infant died in the first weeks of life. The patient had a similarly affected sib, but DNA was not available.
In 2 patients from a family (family 2) with lethal developmental and epileptic encephalopathy-71 (DEE71; 618328), Rumping et al. (2019) identified compound heterozygous mutations in the GLS gene: a c.241C-T transition (c.241C-T, NM_001256310.1), resulting in a gln81-to-ter (Q81X) substitution, and a c.815G-A transition, resulting in an arg272-to-lys (R272K; 138280.0003) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was found in public databases, including gnomAD. The nonsense mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function, and molecular modeling predicted that the R272K variant would destabilize the protein. The patients presented with neonatal refractory seizures, status epilepticus, a burst-suppression pattern on EEG, and respiratory failure. Both died in early infancy. Analysis of newborn Guthrie cards from the patients showed significantly increased glutamine levels compared to controls, suggesting a loss of GLS function.
For discussion of the c.815G-A transition (c.815G-A, NM_001256310.1) in the GLS gene, resulting in an arg272-to-lys (R272K) substitution, that was found in compound heterozygous state in 2 patients with developmental and epileptic encephalopathy-71 (DEE71; 618328) by Rumping et al. (2019), see 138280.0002.
In an 11-year-old girl with infantile cataracts, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID; 618339), Rumping et al. (2019) identified a heterozygous C-to-G transversion (g.191795182C-G, NC_000002.11) in the GLS gene that resulted in substitution of cysteine for serine-482 (S482C). The mutation occurred as a de novo event and was not found in the gnomAD, ClinVar, or ExAC databases. Studies of enzymatic activity demonstrated gain of function.
In 3 unrelated probands with global developmental delay and progressive ataxia due to glutaminase deficiency (GDPAG; 618412), van Kuilenburg et al. (2019) identified a large GCA repeat expansion in the 5-prime untranslated region (UTR) of the GLS gene (chr2:191,745,599-191,745,646, GRCh37) using genome sequencing and triplet repeat-primed PCR. Patient 1 was compound heterozygous for an allele with 680 GCA repeats and a missense mutation (P313L; 138280.0006). Patient 2 was homozygous for the repeat expansion, with 1 allele carrying 900 GCA repeats and the other 1,400 repeats. Patient 3 was compound heterozygous for a 1,500-copy repeat expansion and a frameshift mutation (c.923dupA; 138280.0007). All mutations were transmitted by unaffected parents. In 8,295 untargeted genomes, this short tandem repeat had a median size of 14 repeats, and a bimodal prevalence at 8 and 16 repeats. Of these 8,295 analyzed genomes, 1 was heterozygous for an allele with more than 90 repeats, making the allele frequency of this repeat expansion 6.03 x 10(-5). To determine whether the expansion affected histone modifications of the adjacent GLS promoter, van Kuilenburg et al. (2019) performed chromatin immunoprecipitation assays in fibroblasts from patients 1 and 2 and a control. They observed that patient alleles showed reduced levels of histone modifications characteristic of transcriptionally active regions and were enriched for a histone modification characteristic of transcriptionally silenced regions. The effect was more marked in patient 2, who carried 2 expanded repeat alleles. Van Kuilenburg et al. (2019) concluded that the repeat expansion causes a change in chromatin configuration, which results in decreased transcription. The authors detected a small residual GLS activity in fibroblasts and lymphocytes of the 3 patients, which they suggested might account for the milder phenotype compared with patients with more complete GLS deficiency (see DEE71, 618328).
In a female (patient 1) with global developmental delay, progressive ataxia, and elevated glutamine (GDPAG; 618412), van Kuilenburg et al. (2019) identified compound heterozygosity for a 680-copy GCA repeat in the 5-prime UTR of the GLS gene (138280.0005) and a C-to-T transversion at nucleotide 938 (c.938C-T, NM_014905) in exon 6, resulting in a proline-to-leucine substitution at codon 313 (P313L). This missense variant was absent from gnomAD and was inherited on the paternal allele, which carried 8 copies of the GCA trinucleotide.
In a female (patient 3) with global developmental delay, progressive ataxia, and elevated glutamine (GDPAG; 618412), van Kuilenburg et al. (2019) identified compound heterozygosity for a 1,500-copy expansion of the GLS 5-prime UTR GCA repeat (138280.0005) and a single-basepair duplication (c.923dupA, NM_014905) in exon 6, resulting in a tyr308-to-ter (Y308X) substitution. The c.923dupA mutation was inherited on the maternal allele, which carried 8 copies of the GCA trinucleotide. This variant (rs1212883982) has an allele frequency of 3.984 x 10 (-6) in gnomAD.
Elgadi, K. M., Meguid, R. A., Qian, M., Souba, W. W., Abcouwer, S. F. Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiol. Genomics 1: 51-62, 1999. [PubMed: 11015561] [Full Text: https://doi.org/10.1152/physiolgenomics.1999.1.2.51]
Gao, P., Tchernyshyov, I., Chang, T.-C., Lee, Y.-S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., Dang, C. V. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458: 762-765, 2009. [PubMed: 19219026] [Full Text: https://doi.org/10.1038/nature07823]
Lynch, D. S., Chelban, V., Vandrovcova, J., Pittman, A., Wood, N. W., Houlden, H. GLS loss of function causes autosomal recessive spastic ataxia and optic atrophy. Ann. Clin. Transl. Neurol. 5: 216-221, 2018. [PubMed: 29468182] [Full Text: https://doi.org/10.1002/acn3.522]
Mock, B., Kozak, C., Seldin, M. F., Ruff, N., D'Hoostelaere, L., Szpirer, C., Levan, G., Seuanez, H., O'Brien, S., Banner, C. A glutaminase (Gls) gene maps to mouse chromosome 1, rat chromosome 9 and human chromosome 2. Genomics 5: 291-297, 1989. Note: Erratum: Genomics 5: 957 only, 1989. [PubMed: 2571577] [Full Text: https://doi.org/10.1016/0888-7543(89)90060-8]
Modi, W. S., Pollock, D. D., Mock, B. A., Banner, C., Renauld, J.-C., Van Snick, J. Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) genes by in situ hybridization. Cytogenet. Cell Genet. 57: 114-116, 1991. [PubMed: 1680606] [Full Text: https://doi.org/10.1159/000133126]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Oharo, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Prusiner, S. B. Disorders of glutamate metabolism and neurological dysfunction. Annu. Rev. Med. 32: 512-542, 1981.
Rumping, L., Buttner, B., Maier, O., Rehmann, H., Lequin, M., Schlump, J.-U., Schmitt, B., Schiebergen-Bronkhorst, B., Prinsen, H. C. M. T., Losa, M., Fingerhut, R., Lemke, J. R., Zwartkruis, F. J. T., Houwen, R. H. J., Jans, J. J. M., Verhoeven-Duif, N. M., van Hasselt, P. M., Jamra, R. Identification of a loss-of-function mutation in the context of glutaminase deficiency and neonatal epileptic encephalopathy. JAMA Neurol. 76: 342-350, 2019. [PubMed: 30575854] [Full Text: https://doi.org/10.1001/jamaneurol.2018.2941]
Rumping, L., Tessadori, F., Pouwels, P. J. W., Vringer, E., Wijnen, J. P., Bhogal, A. A., Savelberg, S. M. C., Duran, K. J., Bakkers, M. J. G., Ramos, R. J. J., Schellekens, P. A. W., Kroes, H. Y., and 16 others. GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay. Hum. Molec. Genet. 28: 96-104, 2019. [PubMed: 30239721] [Full Text: https://doi.org/10.1093/hmg/ddy330]
Sahai, S., Vogel, F. Genetic control of platelet glutaminase: a twin study. Hum. Genet. 63: 292-293, 1983. [PubMed: 6682827] [Full Text: https://doi.org/10.1007/BF00284668]
Sahai, S. Glutaminase in human platelets. Clin. Chim. Acta 127: 197-203, 1983. [PubMed: 6825316] [Full Text: https://doi.org/10.1016/s0009-8981(83)80004-7]
van Kuilenburg, A. B. P., Tarailo-Graovac, M., Richmond, P. A., Drogemoller, B. I., Pouladi, M. A., Leen, R., Brand-Arzamendi, K., Dobritzsch, D., Dolzhenko, E., Eberle, M. A., Hayward, B., Jones, M. J., and 33 others. Glutaminase deficiency caused by short tandem repeat expansion in GLS. New Eng. J. Med. 380: 1433-1441, 2019. [PubMed: 30970188] [Full Text: https://doi.org/10.1056/NEJMoa1806627]