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A mutation located at the 5' splice junction sequence of intron 3 in the
p67phox gene causes the lack of p67phox mRNA in a patient with chronic
granulomatous disease
LC Tanugi-Cholley, JP Issartel, J Lunardi, F Freycon, F Morel and PV Vignais
Departement de Biologie Moleculaire et Structurale, Centre d'Etudes
Nucleaires CEA Grenoble, France.
Chronic granulomatous disease (CGD) is due to a functional defect of the
O2(-)-generating NADPH oxidase of neutrophils. Mutations resulting in CGD
have been shown to occur in only four genes, thus identifying the main
components of the oxidase complex, namely the two subunits of a
membrane-bound cytochrome b and two cytosolic factors of activation of 67
kD (p67phox) and 47 kD (p47phox). The present study deals with the
biochemical and genetic analysis of the defect in a patient suffering from
a p67phox-deficient form of CGD. The p67phox deficiency was ascertained by
immunochemistry and the ability of recombinant p67phox to restore NADPH
oxidase activity using a cell-free system of oxidase activation. The
cellular extracts from the proband contained no p67phox protein and no
p67phox mRNA when assayed by Western and Northern blot analysis. However,
reverse transcription of mRNA and subsequent cDNA amplification by
polymerase chain reaction using specific p67phox primers showed that trace
amounts of a p67phox mRNA deleted for exon 3 were synthesized in the
patient immortalized B lymphocytes. Sequence analysis of the genomic DNA
showed a T-to-C transition at position +2 of intron 3. This point mutation
in the consensus 5' splice site of the intron 3 was probably responsible
for lack of accumulation of mRNA and also for the skipping of exon 3
detected in the few mRNA molecules that escaped cellular degradation.
Volume 85,
Issue 1,
pp. 242-249,
01/01/1995
Copyright © 1995 by The American Society of Hematology
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