Evidence for a pretranslational defect in hereditary and acquired
myeloperoxidase deficiency
A Tobler, ME Selsted, CW Miller, KR Johnson, MJ Novotny, G Rovera and HP Koeffler
Department of Medicine, UCLA Medical Center, Los Angeles, CA 90024.
Myeloperoxidase (MPO) is a heme containing enzyme involved in the
oxygen-dependent microbicidal activity of human polymorphonuclear
leukocytes (PMN). Complete hereditary and acquired MPO deficiencies are
defined as lack of peroxidase activity in PMN. Using this criterion, we
studied a patient with complete hereditary MPO deficiency, and a MPO
deficient variant cell line of HL-60 (HL-60-A7), which we used as a model
for acquired MPO deficiency. Western blot analysis showed complete absence
of mature and precursor protein of MPO both in PMN from the patient and in
HL-60-A7 cells. PMN from both parents had one half of normal levels of
these proteins. To study further the molecular basis of this defect, we
isolated an intron specific probe for MPO and used it and a cDNA probe.
Both normal human bone marrow cells and the promyelocytic HL-60 leukemia
cells contained MPO mRNA species of 2.8, 3.3, approximately 4, and greater
than 8 kilobase (kb). The transcripts of greater than 8 and approximately 4
kb contained sequences hybridizing to a probe specific for intron 7 of the
MPO gene. Bone marrow cells of the MPO deficient patient contained two
species of heterogeneous nuclear (hn) RNA of greater than 8 and
approximately 4 kb, but only trace amounts of the normal sized 3.3 kb MPO
mRNA and undetectable 2.8 kb MPO mRNA. HL-60-A7 cells contained both
greater than 8 and approximately 4 kb hnRNA, but only small amounts of
normal sized 2.8 kb MPO mRNA and undetectable levels of the 3.3 kb mRNA.
Southern blot analyses revealed no gross alteration of the MPO gene in both
cases. Our results suggest that a pretranslational defect is one mechanism
leading to MPO deficiency.
Volume 73,
Issue 7,
pp. 1980-1986,
05/15/1989
Copyright © 1989 by The American Society of Hematology
