A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia

gamma-Glutamylcysteine synthetase (GCS) catalyzes the initial and rate-limi ting step in the biosynthesis of glutathione. gamma-GCS consists of a heavy and a light subunit encoded by separate genes. Hereditary deficiency of GC S has been reported in 6 patients with hemolytic anemia and low erythrocyte levels of glutathione and gamma-glutamylcysteine, In addition, 2 patients also had generalized aminoaciduria and developed neurologic symptoms. We ha ve examined a Dutch kindred with 1 suspected case of GCS deficiency. The pr oband was a 68-year-old woman with a history of transient jaundice and comp ensated hemolytic anemia. One of her grandchildren was also GCS deficient; he was 11 years old and had a history of neonatal jaundice. The enzyme defe ct was confirmed and GCS activity was found to be less than 2% of normal in the erythrocytes of both patients. The complementary DNA (cDNA) for the he avy subunit of GCS was sequenced in these patients and in several members o f the family. The proband and her GCS-deficient grandson were identified as homozygous for a 473C --> T substitution, changing codon 158 from CCC for proline into CTC for leucine, Several family members with half-normal GCS a ctivity in their erythrocytes were heterozygous for the mutation. (Blood, 2 000;95:2193-2197) (C) 2000 by The American Society of Hematology.