Chronic granulomatous disease and glutathione peroxidase deficiency,
revisited
PE Newburger, SE Malawista, MC Dinauer, T Gelbart, RC Woodman, S Chada, Q Shen, G van Blaricom, PG Quie and JT Curnutte
Department of Pediatrics, University of Massachusetts Medical School,
Worcester 01655.
We have restudied two kindreds that formed the basis of the original report
of autosomal recessive chronic granulomatous disease (CGD) associated with
leukocyte glutathione peroxidase deficiency. Case 1 from the original study
and the surviving brother of the originally reported case 2 both have
severe CGD, with no detectable respiratory burst activity in purified
intact neutrophils. However, their leukocytes exhibit normal glutathione
peroxidase enzyme activity and gene expression. Examination of phagocyte
nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase components
known to be defective in CGD reveals no detectable cytochrome b558 nor any
membrane activity in a cell-free NADPH oxidase assay system. Molecular
analysis of the genes encoding cytochrome b558 subunits shows, in case 1, a
C-->T substitution at nucleotide 688 of the gene encoding the gp91-phox
subunit of cytochrome b558, resulting in a termination signal in place of
Arginine-226. Levels of gp91-phox mRNA are markedly decreased despite
normal levels of gene transcription, indicating a post- transcriptional
effect of the nonsense mutation on mRNA processing or stability. The
X-linked form of CGD developed in this cytogenetically normal female due to
the uniform inactivation of the normal X chromosome in her granulocytes,
indicated by the expression in her granulocyte mRNA of only one allele of a
glucose-6-phosphate dehydrogenase polymorphisms for which she is
heterozygous in genomic DNA. Case 2 (of the present study) has distinct
mutations in each allele of the p22-phox gene.(ABSTRACT TRUNCATED AT 250
WORDS)
Volume 84,
Issue 11,
pp. 3861-3869,
12/01/1994
Copyright © 1994 by The American Society of Hematology
