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Next Article 
Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2193-2196
PLENARY PAPER
A missense mutation in the heavy subunit of  -glutamylcysteine
synthetase gene causes hemolytic anemia
Ellinor Ristoff,
Camilla Augustson,
Judy Geissler,
Thea de Rijk,
Katarina Carlsson,
Jia-Li Luo,
Kerstin Andersson,
Ron S. Weening,
Rob van Zwieten,
Agne Larsson, and
Dirk Roos
From the Department of Pediatrics, Karolinska Institute, Huddinge
University Hospital, Huddinge, Sweden; the Central Laboratory of the
Netherlands Red Cross Blood Transfusion Service and Laboratory of
Experimental and Clinical Immunology, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands; the Department of
Anesthesiology, Karolinska Institute, Huddinge University Hospital,
Huddinge, Sweden; and the Emma Children's Hospital, Academic Medical
Center, University of Amsterdam, Amsterdam, The Netherlands.
 -Glutamylcysteine synthetase (GCS) catalyzes the initial and
rate-limiting step in the biosynthesis of glutathione. -GCS consists
of a heavy and a light subunit encoded by separate genes. Hereditary
deficiency of GCS has been reported in 6 patients with hemolytic anemia
and low erythrocyte levels of glutathione and -glutamylcysteine. In
addition, 2 patients also had generalized aminoaciduria and developed
neurologic symptoms. We have examined a Dutch kindred with 1 suspected
case of GCS deficiency. The proband was a 68-year-old woman with a
history of transient jaundice and compensated hemolytic anemia. One of
her grandchildren was also GCS deficient; he was 11 years old and had a
history of neonatal jaundice. The enzyme defect 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 heavy subunit of GCS was sequenced in these patients and in several members of 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 activity in their erythrocytes were heterozygous for
the mutation.
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