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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 666-673
Four novel mutations in the gene encoding gp91-phox of
human NADPH oxidase: consequences for oxidase assembly
J. H. W. Leusen,
C. Meischl,
M. H. M. Eppink,
P. M. Hilarius,
M. de Boer,
R. S. Weening,
A. Åhlin,
L. Sanders,
D. Goldblatt,
H. Skopczynska,
E. Bernatowska,
J. Palmblad,
A. J. Verhoeven,
W. J. H. van
Berkel, and
D. Roos
From the Central Laboratory of The Netherlands Red Cross Blood
Transfusion Service, the Laboratory of Experimental and Clinical
Immunology, and the Emma Children's Hospital, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands; the Department of
Biomolecular Sciences, Laboratory of Biochemistry, Wageningen
University, Wageningen, The Netherlands; Wilhelmina
Children's Hospital, Utrecht, The Netherlands; the Department of
Pediatrics, Sachs' Children's Hospital, Stockholm Söder
Hospital, Stockholm, Sweden; the Department of Medicine, the Center for
Inflammation and Hematology Research, Huddinge University Hospital,
Huddinge, Sweden; the Department of Clinical Immunology,
Children's Memorial Hospital, Warsaw, Poland; and the Institute of
Child Health, University College London, London, Great Britain.
The superoxide-forming nicotinamide adenine dinucleotide phosphate
reduced (NADPH) oxidase of human phagocytes comprises membrane-bound and cytosolic proteins, which, upon cell activation, assemble on the
plasma membrane to form the active enzyme. Patients with chronic
granulomatous disease (CGD) are defective in one of the phagocyte
oxidase (phox) components, p47-phox or
p67-phox, which reside in the cytosol of resting phagocytes, or
gp91-phox or p22-phox, which constitute the
membrane-bound cytochrome b558. In four X-linked CGD patients we have identified novel missense mutations in
CYBB, the gene encoding gp91-phox. These mutations were
associated with normal amounts of nonfunctional cytochrome
b558 in the patients' neutrophils. In
phorbol-myristate-stimulated neutrophils and in a cell-free
translocation assay with neutrophil membranes and cytosol, the
association of p47-phox and p67-phox with
the membrane fraction of the cells with Cys369 Arg,
Gly408Glu, and Glu568 Lys substitutions was
strongly disturbed. Only a Thr341Lys substitution, residing
in a region of gp91-phox involved in flavin adenine
dinucleotide (FAD) binding, supported a normal translocation. Thus, the
introduction or reversal of charge at residues 369, 408, and 568 in
gp91-phox destroys the correct binding of p47-phox and
p67-phox to cytochrome b558. Based on
mutagenesis studies of structurally related flavin-dependent oxidoreductases, we propose that the Thr341Lys substitution
results in impaired hydride transfer from NADPH to FAD. Because we
found no electron transfer in solubilized neutrophil plasma membranes from any of the four patients, we conclude that all four amino acid
replacements are critical for electron transfer. Apparently, an
intimate relation exists between domains of gp91-phox involved in electron transfer and in p47/p67-phox binding.
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