Glutathione synthetase deficiency

Njålsson, Runa

doi:10.1007/s00018-005-5163-7

Cited by 72 publications

(66 citation statements)

References 90 publications

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“…The glutathione synthetase deficiency (MIM 266130) is the best characterized and the most common of the inborn errors of GSH metabolism (Njalsson 2005;Ristoff and Larsson 2007). It presents with a wide spectrum of clinical signs.…”

Section: Introductionmentioning

confidence: 99%

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

et al. 2012

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The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH metabolism, whereas the OPLAH deficiency is questioned whether it is a disorder or just a biochemical condition with no adverse clinical effects. Recently, the first human OPLAH mutation (p.H870Pfs) was reported in homozygosis in two siblings who suffered from 5-oxoprolinuria with a benign clinical course. We report two unrelated patients who manifested massive excretion of 5-oxoproline in urine. In both probands, the blood GSH levels were normal and no mutations were found in the GSS gene. The mutational screening of the OPLAH gene, which included the codified sequences, the intronic flanking sequences, the promoter sequence, and a genetic analysis in order to detect large deletions and/or duplications, showed that each patient only harbors one missense mutation in heterozygosis. The in silico analyses revealed that each one of these OPLAH mutations, p.S323R and p.V1089I, could alter the proper function of this homodimeric enzyme. In addition, clinical symptoms manifest in these two probands were not related to GSH cycle defects and, therefore, this study provides further evidence that oxoprolinuria may present as epiphenomenon in several pathological conditions and confound the final diagnosis.

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Section: Introductionmentioning

confidence: 99%

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

et al. 2012

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“…Biochemical diagnosis is based on the organic aciduria profile, cellular glutathione quantification, and enzymatic assay in RBC and nucleated cells. 4 In our case, the patient presented with a mild form of GSD, revealed by isolated HA. In this form, only some of the affected patients present with concomitant 5-oxoprolinuria, and involvement of a trigger factor in the anemic episode is rarely described.…”

Section: Discussionmentioning

confidence: 64%

“…GSD can be divided into 3 clinical forms: a mild form, presenting with HA and variable 5-oxoprolinuria; a moderate form, associated with HA, constant 5-oxoprolinuria, and metabolic acidosis; and the severe form, associated with HA, constant 5-oxoprolinuria, metabolic acidosis, and neurologic defects. 4,7,8 Pathophysiology is explained by a decreased concentration of GSH due to the mutated GSS enzyme, which is unable to fulfill its role in the γ-glutamyl cycle. 4 GSH exerts negative feedback on γ-glutamyl cysteine synthetase, thus regulating its own formation (Fig 2A).…”

Section: Discussionmentioning

confidence: 99%

“…4,7,8 Pathophysiology is explained by a decreased concentration of GSH due to the mutated GSS enzyme, which is unable to fulfill its role in the γ-glutamyl cycle. 4 GSH exerts negative feedback on γ-glutamyl cysteine synthetase, thus regulating its own formation (Fig 2A). 9 When GSS is deficient, as in GSD, negative feedback is lost, leading to an increase in γ-glutamyl cysteine and thus an increase in 5-oxoproline via the γ-glutamyl cyclotransferase pathway.…”

Section: Discussionmentioning

confidence: 99%

“…2 Among them, glutathione synthetase (GSS) is involved in the synthesis of glutathione (GSH), a strong antioxidant. 3 GSH depletion can be constitutive (genetic defect) 4 or induced by different trigger factors (eg, drugs, severe sepsis, malnutrition). 5,6 Hereditary glutathione synthetase deficiency (GSD) is classified into 3 phenotypes, from a mild form with isolated HA to a severe form with HA, constant 5-oxoprolinuria, metabolic acidosis, abstract Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia.…”

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confidence: 99%

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Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

et al. 2016

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Hemolytic anemia (HA) of the newborn should be considered in cases of rapidly developing, severe, or persistent hyperbilirubinemia. Several causes of corpuscular hemolysis have been described, among which red blood cell enzyme defects are of particular concern. We report a rare case of red blood cell enzyme defect in a male infant, who presented during his first months of life with recurrent and isolated neonatal hemolysis. All main causes were ruled out. At 6.5 months of age, the patient presented with gastroenteritis requiring hospitalization; fortuitously, urine organic acid chromatography revealed a large peak of 5-oxoproline. Before the association between HA and 5-oxoprolinuria was noted, glutathione synthetase deficiency was suspected and confirmed by a low glutathione synthetase concentration and a collapse of glutathione synthetase activity in erythrocytes. Moreover, molecular diagnosis revealed 2 mutations in the glutathione synthetase gene: a previously reported missense mutation (c.[656A>G]; p.[Asp219Gly]) and a mutation not yet described in the binding site of the enzyme (c.[902T>C]; p.[Leu301Pro]). However, 15 days later, a control sample revealed no signs of 5-oxoprolinuria and the clinical history discovered administration of acetaminophen in the 48 hours before hospitalization. Thus, in this patient, acetaminophen exposure allowed the diagnosis of a mild form of glutathione synthetase deficiency, characterized by isolated HA. Early diagnosis is important because treatment with bicarbonate, vitamins C and E, and elimination of trigger factors are recommended to improve long-term outcomes. Glutathione synthetase deficiency should be screened for in cases of unexplained newborn HA.

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Overexpression of the regulatory subunit of glutamate‐cysteine ligase enhances monoclonal antibody production in CHO cells

Orellana

Marcellin

Gray

et al. 2017

Biotech & Bioengineering

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For decades, Chinese hamster ovary (CHO) cells have been the preferred host for therapeutic monoclonal antibody (mAb) production; however, increasing mAb titer by rational engineering remains a challenge. Our previous proteomic analysis in CHO cells suggested that a higher content of glutathione (GSH) might be related to higher productivity. GSH is an important antioxidant, cell detoxifier, and is required to ensure the formation of native disulfide bonds in proteins. To investigate the involvement of GSH in mAb production, we generated stable CHO cell lines overexpressing genes involved in the first step of GSH synthesis; namely the glutamate-cysteine ligase catalytic subunit (Gclc) and the glutamate-cysteine ligase modifier subunit (Gclm). The two genes were reconstructed from our RNA-Seq de novo assembly and then were functionally annotated. Once the sequences of the genes were confirmed using proteogenomics, a transiently expressed mAb was introduced into cell lines overexpressing either Gclc or Gclm. The new cell lines were compared for mAb production to the parental cell line and changes at the proteome level were measured using SWATH. As per our previous proteomics observations, overexpressing Gclm improved productivity, titer, and the frequency of high producer clones by 70%. In contrast, overexpressing Gclc, which produced a higher amount of GSH, did not increase mAb production. We show that GSH cannot be linked to higher productivity and that Gclm may be controlling other cellular processes involved in mAb production yet to be elucidated. Biotechnol. Bioeng. 2017;114: 1825-1836. © 2017 Wiley Periodicals, Inc.

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Glutathione synthetase deficiency

Cited by 72 publications

References 90 publications

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

Recurrent Isolated Neonatal Hemolytic Anemia: Think About Glutathione Synthetase Deficiency

Overexpression of the regulatory subunit of glutamate‐cysteine ligase enhances monoclonal antibody production in CHO cells

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