Origin of mutations in two families with X-linked chronic granulomatous
disease
U Francke, HD Ochs, BT Darras and A Swaroop
Department of Genetics, Stanford University Medical Center, CA 94305- 5428.
The most common X-linked recessive form of chronic granulomatous disease
(X-CGD) is characterized by the absence of cytochrome b558 in neutrophils.
In a rare variant form of X-CGD, cytochrome b558 is present but not
functional. The gene (locus symbol CYBB) was localized to band Xp21 by
studies of patients with small chromosome deletions. The gene was cloned
based on its location and found to encode the 91-Kd subunit of the
cytochrome b558 complex. Most female carriers for X-CGD can be identified
by their X-inactivation mosaicism; on average 50% of their neutrophils
express the mutant phenotype and fail to reduce nitroblue tetrazolium
(NBT). In 2 of 4 families studied, the maternal grandmothers had normal NBT
tests, suggesting either nonrandom X- inactivation or new mutations.
Restriction fragment length polymorphism analysis using closely linked
flanking markers or the NsiI polymorphism detected by the CYBB probe
itself, allowed us to identify the X chromosome carrying the mutation as
derived from a healthy NBT-positive maternal grandfather. The mothers of
the affected boys must have received a paternal X chromosome carrying a new
mutation, consistent with the maternal grandmothers' normal NBT tests. In
all of eight potential carriers studied, the results of the NBT and DNA
marker testing were in complete agreement. Prenatal diagnosis by DNA
testing can be performed in early gestation obviating the need for fetal
blood sampling.
Volume 76,
Issue 3,
pp. 602-606,
08/01/1990
Copyright © 1990 by The American Society of Hematology
