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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2505-2514
Molecular Characterization of Autosomal Recessive Chronic Granulomatous
Disease Caused by a Defect of the Nicotinamide Adenine Dinucleotide
Phosphate (Reduced Form) Oxidase Component
p67-phox
Pablo J. Patiño,
Julie Rae,
Deborah Noack,
Rich Erickson,
Jiabing Ding,
Diana García de Olarte, and
John
T. Curnutte
From the Department of Immunology, Genentech, Inc, South San
Francisco, CA; the Laboratory of Immunology, Department of Microbiology
and Parasitology, School of Medicine, University of Antioquia,
Medellin, Colombia; and the Scripps Reference Laboratory and Department
of Molecular and Experimental Medicine, The Scripps Research Institute,
La Jolla, CA.
Chronic granulomatous disease (CGD) is a rare inherited disorder of
phagocytes in which defective production of microbicidal oxidants leads
to severe recurrent infections. CGD is caused by mutations in any of 4 genes encoding components of nicotinamide adenine dinucleotide
phosphate (reduced form; NADPH) oxidase, the multisubunit enzyme that
produces the precursor of these oxidants, superoxide. Approximately 5%
of CGD patients have an autosomal recessive form of disease caused by a
severe deficiency of p67-phox, a 526-amino acid subunit of the
oxidase that appears to regulate electron transport within the enzyme.
Here we report the biochemical and molecular characterization of 6 unrelated kindreds with p67-phox deficiency. These studies show
that, as in gp91-phox and p22-phox deficiencies, the
p67-phox CGD patients show a high degree of heterogeneity in
the genetic defects that underlie their disease. Five different mutant
alleles were identified: (1) a nonsense mutation in exon 4 (C304  T); (2) a 5-nucleotide (nt) deletion in
exon 13 (nts 1169-1173); (3) a splice mutation in the first nucleotide
of intron 4 (G A); (4) a deletion of 1 nt in exon 9 (A728); and (5) a 9-nt in-frame deletion in exon 2 (nts
55-63). The splice mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 apparently unrelated families (both of
Palestinian origin). Homozygosity was present in 4 of the kindreds, 2 of which had consanguineous parentage. In the isolated neutrophils of
each of the affected patients in the 6 kindreds, there was no
measurable respiratory burst activity and no p67-phox protein detected by immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot studies. Thus, this heterogeneous group of mutations in p67-phox all lead to marked instability of mRNA or protein (or both) that results in the complete loss of NADPH
oxidase activity.
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