Abstract
Chronic granulomatous disease (CGD) is a rare
inherited disorder in which phagocytes lack NADPH
oxidase activity. The most common form is caused by
mutations in the CYBB gene encoding gp91phox protein,
the heavy chain of cytochrome b558, which is the redox
element of NADPH oxidase. In some rare cases, the
mutated gp91phox is normally expressed but no NADPH
oxidase can be detected. This type of CGD is called X91+
CGD. We have previously reported an X+ CGD case with
a double-missense mutation in gp91phox. Transgenic
PLB-985 cells have now been made to study the impact
of each single mutation on oxidase activity and assembly
to rule out a possible new polymorphism in the CYBB
gene. The His303Asn/Pro304Arg gp91phox transgenic
PLB-985 cells exactly mimic the phenotype of the
neutrophils of the X+ CGD patient. The His303Asn
mutation is sufficient to inhibit oxidase activity in intact
cells and in a broken cell system, whereas in the
Pro304Arg mutant, residual activity suggests that the
Pro304Arg substitution is less devastating to oxidase
activity than the His303Asn mutation. The study of
NADPH oxidase assembly following the in vitro and in
vivo translocation of cytosolic factors p47phox and
p67phox has demonstrated that, in the double mutant
and in the His303Asn mutant, NADPH oxidase assembly
is abolished, although the translocation is only attenuated
in Pro304Arg mutant cells. Thus, even though the
His303Asn mutation has a more severe inhibitory effect
on NADPH oxidase activity and assembly than the
Pro304Arg mutation, neither mutation can be considered
as a polymorphism.
Original language | English |
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Pages (from-to) | 418-427 |
Journal | Human Genetics |
Volume | 115 |
DOIs | |
Publication status | Published - 2004 |
Keywords
- double missense mutation
- human nadph oxidase
- cytochrome b(558)
- respiratory burst
- human-neutrophils
- gp91-phox gene
- point mutation
- gp91(phox)
- protein
- expression