Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency

Abstract

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.

Kinetic properties of missense mutations in patients with glutathione synthetase deficiency

“…The mutations and the heterogeneous clinical symptoms of the patients studied have been described previously [8][9][10]. The four patients are compound heterozygotes for missense mutations affecting amino acid residues that are conserved between rats and humans.…”

“…The human enzyme functions as a homodimer, with subunits containing 474 amino acid residues [6], encoded by a gene located on chromosome 20q11.2 [7]. Eighteen different mutations from 16 patients with GS deficiency have been described [8][9][10]. Many of these mutations affect residues that are within the protein core and active-site regions [11].…”

Controlled Growth of Gold Nanostars: Effect of Spike Length on SERS Signal Enhancement

“…[13][14][15] Highly sensitive techniques, such as HPLC,e lectrochemical methods, capillary electrophoresis and fluorescencemethods, are available for the detection of GSH. GSH is ab iologically important compound that acts as ab iomarker for severald iseases, such as Parkinson's disease, liver diseases,c ystic fibrosis, sickle-cell anaemia, AIDS, Alzheimer'sd isease and leukaemia.…”

Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

“…Missense mutations will account for the phenotype in the majority of patients with severe GS deficiency (Dahl et al, 1997). A 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491→A homozygous splice site mutation, and a C847→T (Arg283→ Cys) mutation in exon 9 are described in patients with GS deficiency and Fanconi nephropathy (Al-Jishi et al, 1999). A homozygous state for 656 A→G, a 808 T→C mutation of GS gene in patients with chronic haemolysis and markedly reduced erythrocytes was found in Spain (Corrons, et al, 2001).…”