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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2890-2894
The Molecular Basis of a Case of  -Glutamylcysteine Synthetase
Deficiency
Ernest Beutler,
Terri Gelbart,
Takahito Kondo, and
Alison T. Matsunaga
From the Department of Molecular and Experimental Medicine, The
Scripps Research Institute, La Jolla, CA; the Department of
Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease
Institute, Nagasaki University School of Medicine, Nagasaki, Japan; and
the Children's Hospital Medical Center, Oakland, CA.
 -Glutamylcysteine synthetase catalyzes the first step in
glutathione synthesis. The enzyme consists of 2 subunits, heavy and
light, with the heavy subunit serving as the catalytic subunit. A
patient with hemolytic anemia and low red blood cell glutathione levels
was found to have a deficiency of -glutamylcysteine synthetase activity. Examination of cDNA from the patient and her mother showed
that she was homozygous and that her mother was heterozygous for a
A T transversion at nt1109 producing a deduced amino acid change of His370Leu. The partial genomic structure of the catalytic subunit of -glutamylcysteine synthetase (GLCLC) was
determined, providing some intron/exon boundaries to make it possible
to sequence an affected part of the coding region from genomic DNA. The
1109AT mutation was not present in the DNA of 38 normal
subjects. In the course of these studies we found a diallelic
polymorphism in nt +206 of an intron and another polymorphism that
consisted of a duplication of a CAGC at cDNA nt1972-1975 in the
3' untranslated region. The 2 polymorphisms were found to be only
in partial linkage disequilibrium.
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