Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene

Njålsson, Runa; Carlsson, Katarina Steen; Winkler, Andreas; Larsson, Agne; Norgren, Svante

doi:10.1002/humu.9199

Cited by 22 publications

(19 citation statements)

References 9 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutation analyses establish the diagnosis. Because of the high percentage of splice mutations (approximately 40%), we recommend that mutation analyses at the genomic level should be complemented with analyses of RNA transcripts [39]. Interestingly, patients with splice mutations and undetectable levels of protein using a polyclonal GSS-specific antibody show residual enzyme activity, albeit very low [39].…”

Section: Diagnosticsmentioning

confidence: 99%

“…4); however, one-third of the mutations described so far (comprising >40% of the analysed alleles, siblings counted only once) are splice mutations [57]. These mutations cause exon skipping, pseudoexons, partial exclusion of exonic sequences and retention of downstream intronic sequences [39]. In total, 16 missense mutations, 9 splice mutations, 2 deletions, one insertion and one nonsense mutation have been identified in GSS deficiency [25].…”

Section: Molecular Aspects Of Gssmentioning

confidence: 99%

See 1 more Smart Citation

Glutathione synthetase deficiency

Njålsson

2005

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Glutathione (GSH), one of the most important antioxidants in the eukaryotic organism, is synthesized in a two-step procedure where the last step is catalysed by the enzyme glutathione synthetase (GSS). GSS deficiency is inherited autosomal recessively, and patients with this disease can be divided into three groups, according to their clinical phenotype. Mildly affected patients have mutations affecting the stability of the enzyme, causing a compensated haemolytic anaemia; moderately affected patients have, in addition, metabolic acidosis; and severely affected patients also develop neurological defects and show increased susceptibility to bacterial infections. Moderately and severely affected patients have mutations that compromise the catalytic properties of the enzyme. 5-Oxoprolinuria appears in all three groups, but is more pronounced in the two latter groups. Today, no cure can be offered these patients; they are given vitamins C and E to boost their antioxidant levels, and bicarbonate to correct metabolic acidosis.

show abstract

Section: Diagnosticsmentioning

confidence: 99%

Section: Molecular Aspects Of Gssmentioning

confidence: 99%

Glutathione synthetase deficiency

Njålsson

2005

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…A group of 41 patients (26 males and 15 females, including 8 sib pairs) from 33 families was investigated; 8 patients had not been described elsewhere, whereas 33 had been reported in previous publications (Shi et al 1996;Dahl et al 1997;Al-Jishi et al 1999;Corrons et al 2001;Ristoff et al 2001Nja˚lsson et al 2003). The patients originated from Europe, USA, Africa, the Middle East, and Australia; 12 patients had consanguineous parents.…”

Section: Patients and Clinical Phenotypementioning

confidence: 99%

Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency

et al. 2005

Self Cite

View full text Add to dashboard Cite

Glutathione synthetase (GS) deficiency is a rare autosomal recessive disorder. The clinical phenotype varies widely, and nearly 30 different mutations in the GSS gene have been identified. In the present study, genotype, enzyme activity, metabolite levels and clinical phenotype were evaluated in 41 patients from 33 families. From some of the patients, data on glutathione (GSH) levels and gamma-glutamylcysteine levels in cultured fibroblasts were also available. Twenty-seven different mutations were found: 14 missense, 9 splice, 2 deletions, 1 insertion and 1 nonsense mutation. Twenty-three patients were homozygous and 18 were compound heterozygous. The moderate and severe clinical phenotypes could not be distinguished based on enzyme activity, GSH or gamma-glutamylcysteine levels in cultured fibroblasts. However, in fibroblasts, the residual GS activity was correlated with the GSH level. All mutations causing frameshifts, premature stop codons or aberrant splicing were associated with moderate or severe clinical phenotypes including haemolytic anaemia, 5-oxoprolinuria, and (in several forms) neurodevelopmental signs. The data indicate that additional genetic or environmental factors modify at least the moderate and severe phenotypes and that the clinical classification given to the patients may be influenced by variation in follow-up. The type of mutation involved can, to some extent, predict a mild versus a more severe phenotype.

show abstract

“…The most frequent hallmarks are 5-oxoprolinuria, metabolic acidosis and hemolytic anemia, and in severely affected patients, the central nervous system is affected. This deficiency is caused by mutations in the GSS gene and more than 30 mutations have been described which are transmitted in an autosomal recessive fashion (Al-Jishi et al 1999;Dahl et al 1997;Njalsson et al 2003;Shi et al 1996). Heterozygous carriers of GSS mutations are healthy and show an enzyme activity of 55% of the normal mean and normal levels of GSH .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene

Cited by 22 publications

References 9 publications

Glutathione synthetase deficiency

Glutathione synthetase deficiency

Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency

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

Contact Info

Product

Resources

About