Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of γ-glutamylcysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5’ untranslated region

Walsh, Anne C.; Li, W.; Rosen, David I.; Lawrence, Daniel A.

doi:10.1159/000134447

Cited by 33 publications

(23 citation statements)

References 6 publications

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“…As well, a series of GAG repeats has been identified in the 5Ј untranslated region (UTR) located 10 to 30 bp upstream from the ATG translational start codon. 5,28 Five alleles have been reported, each with a different frequency of occurrence depending on ethnic background: A1, 7 GAGs; A2, 8 GAGs; A3, 9 GAGs; A4, 10 GAGs; and A5, 4 GAGs. Of our 2 patient samples, one was found to have allele A1 and the other allele A2.…”

Section: Discussionmentioning

confidence: 99%

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A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production

Hamilton

Alaoui‐Jamali

et al. 2003

Blood

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␥-Glutamylcysteine synthetase (␥-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)-dependent ligation of glutamate and cysteine. ␥-GCS consists of a catalytic (␥-GCS H ) and modifier (␥-GCS L ) subunit. Hereditary deficiency of ␥-GCS has been reported in a small number of patients and is associated with low erythrocyte levels of ␥-GCS and GSH leading to hemolytic anemia. Here we report a novel ␥-GCS H mutation, isolated from the cDNA of 2 related patients diagnosed with ␥-GCS deficiency. Each was found to be homozygous for a C>T missense mutation at nucleotide 379, encoding for a predicted Arg127Cys amino acid change. Computerized structure modeling identified that the mutated amino acid lies within a cleft on the protein surface of ␥-GCS H , and the border of this cleft was shown to contain Cys249, an evolutionarily conserved residue that has been proven to lie near the binding site of ␥-GCS H . Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type. (Blood. 2003; 102:725-730)

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Section: Discussionmentioning

confidence: 99%

“…It is encoded by a gene located on chromosome 6p12. 5 The light subunit (31 kDa) serves a modifying function, increasing the affinity of ␥-GCS for its substrates, glutamate and cysteine. It is encoded by a gene on chromosome 1p21.…”

Section: Introductionmentioning

confidence: 99%

A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production

Hamilton

Alaoui‐Jamali

et al. 2003

Blood

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“…Variations in the expression of the c-GCS gene in humans may represent a new susceptibility factor in oxidantinduced injury, which is thought to occur as part of the pathogenesis in COPD. It has been proposed that a GAG trinucleotide repeat polymorphism occurs in the 5'-coding and noncoding regions of the c-GCS-HS gene [175]. Genetic analysis of 50 unrelated Caucasians identified three alleles as follows: A1 (nine repeats, 35% frequency), A2 (eight repeats, 11% frequency), and A3 (seven repeats, 54% frequency).…”

Section: Role Of C-glutamylcysteine Synthetase In Genetic Susceptibilmentioning

confidence: 99%

“…The c-GCS subunit genes are located on separate chromosomes and expression of their mRNA varies considerably between different tissues [175,177,178]. Human c-GCS-HS is located on chromosome 6 (6p12) and c-GCS-LS on chromosome 1 (1p21) [177±179].…”

Section: Role Of C-glutamylcysteine Synthetase In Genetic Susceptibilmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

807

562

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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“…GCL is composed of two subunits, a catalytic subunit (GCLC) and a modifier subunit (GCLM) (17,18). The 5Ј-untranslated region of GCLC mRNA (NM_001498) has been shown to contain a polymorphic guanine-adenine-guanine (GAG) trinucleotide repeat (TNR) just upstream of the translation start codon (19). This GAG TNR polymorphism is associated with variable levels of GSH in human cells lines, with 7 GAG TNR associated with the lowest GSH levels, 8 GAG TNR associated with intermediate GSH levels, and 9 GAG TNR associated with the highest GSH levels (20).…”

mentioning

confidence: 99%

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

McKone

Shao

Frangolias

et al. 2006

Am J Respir Crit Care Med

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Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury. Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease. Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype. Measurements and Main Results

show abstract

Genetic mapping of GLCLC, the human gene encoding the catalytic subunit of γ-glutamylcysteine synthetase, to chromosome band 6p12 and characterization of a polymorphic trinucleotide repeat within its 5’ untranslated region

Cited by 33 publications

References 6 publications

A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production

A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production

Oxidative stress and regulation of glutathione in lung inflammation

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

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