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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 2955-2962
Molecular Basis and Enzymatic Properties of Glucose 6-Phosphate
Dehydrogenase Volendam, Leading to Chronic Nonspherocytic Anemia,
Granulocyte Dysfunction, and Increased Susceptibility to Infections
Dirk Roos,
Rob van Zwieten,
Juul T. Wijnen,
Felix Gómez-Gallego,
Martin de Boer,
David Stevens,
Claudia J. Pronk-Admiraal,
Thea de Rijk,
Cornelis J.F. van Noorden,
Ron S. Weening,
Tom J. Vulliamy,
J. Eduard Ploem ,
Philip J. Mason,
José M. Bautista,
P. Meera Khan, and
Ernest Beutler
From the Central Laboratory of the Netherlands Red Cross Blood
Transfusion Service and Laboratory for Experimental and Clinical
Immunology, and the Department of Cell Biology and Histology, and
Department of Pediatrics, Emma Children's Hospital, Academic Medical
Center, University of Amsterdam, Amsterdam; Department of Human
Genetics, University of Leiden, Leiden; Laboratory of Clinical
Chemistry, Hematology and Immunology, Medical Center Alkmaar, Alkmaar;
Department of Hematology, Sint Lucas Hospital, Amsterdam, The
Netherlands; Department of Biochemistry and Molecular Biology IV,
University Complutense de Madrid, Madrid, Spain; Department of
Haematology, Imperial College School of Medicine, Hammersmith Hospital,
London; Royal Postgraduate Medical School, University of London,
London, United Kingdom; and the Department of Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla,
CA.
We have investigated the blood cells from a woman with a low degree
of chronic nonspherocytic hemolytic anemia and frequent bacterial
infections accompanied by icterus and anemia. The activity of glucose
6-phosphate dehydrogenase (G6PD) in her red blood cells (RBCs) was
below detection level, and in her leukocytes less than 3% of normal.
In cultured skin fibroblasts, G6PD activity was approximately 15% of
normal, with 4- to 5-fold increased Michaelis constant (Km) for NADP
and for glucose 6-phosphate. Activated neutrophils showed a decreased
respiratory burst. Family studies showed normal G6PD activity in the
RBCs from all family members, including both parents and the 2 daughters of the patient. Sequencing of polymerase chain reaction
(PCR)-amplified genomic DNA showed a novel, heterozygous
514C T mutation, predicting a Pro172Ser replacement.
Analysis of G6PD RNA from the patient's leukocytes and fibroblasts
showed only transcripts with the 514CT mutation. This was
explained by the pattern of X-chromosome inactivation, studied by means
of the human androgen receptor (HUMARA) assay, which proved to be
skewed in the patient, her mother, and one of the patient's daughters.
Thus, the patient has inherited a de novo mutation in G6PD from her
father and an X-chromosome inactivation determinant from her mother,
causing exclusive expression of the mutated G6PD allele. Purified
mutant protein from an Escherichia coli expression system
showed strongly decreased specific activity, increased Km for NADP and
for glucose 6-phosphate, and increased heat lability, which indicates
that the defective phenotype is due to 2 synergistic molecular
dysfunctions: decreased catalytic efficiency and protein instability.
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