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Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency
M Kizaki, CW Miller, ME Selsted and HP Koeffler
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School
of Medicine 90048.
Myeloperoxidase (MPO), present in the azurophilic granules of
polymorphonuclear leukocytes, is a myeloid enzyme whose synthesis is
restricted to promyelocytes. Complete hereditary MPO deficiency affects 1
in 2,000 to 4,000 individuals; however, the genetic cause of this defect is
unclear. We have determined the molecular basis of MPO deficiency in one
individual (SQ). Granulocytes of SQ had no MPO activity, and had complete
absence of mature and precursor MPO protein by Western blotting. Scanning
MPO gene structure by Southern blotting detected a novel BgI II fragment in
SQ; no other alteration in gross gene structure was detected. We
hypothesized that a single base pair mutation formed a new BgI II
restriction site, and that this occurred in exon 10 of MPO gene. As
predicted, exon 10 from SQ was cleaved by BgI II, but DNA from the normal
patients and five other MPO-deficient patients was not cleaved by this
enzyme. Direct sequencing of the polymerase chain reaction (PCR) product of
exon 10 showed a C to T substitution at codon 569 in exon 10, resulting in
arginine (CGG) to tryptophan (TGG) substitution and creating a novel BgI II
site. The mutation was homozygous, as shown by both sequencing and Southern
blotting, and no other alterations in base sequence were detected. To
determine the frequency of this mutation, DNA was collected from 400 normal
individuals, and the presence of the mutation was examined by digesting
with BgI II after amplifying exon 10 by PCR. No other case with the novel
BgI II site was detected, suggesting that this is not a restriction
fragment length polymorphism. The rest of the coding region of the MPO gene
was sequenced in DNA from SQ, as well as from the five other MPO-deficient
individuals and one normal person; no other mutations were found. Our
results suggest that a point mutation at codon 569 of MPO gene represents
one molecular form of MPO deficiency.
Volume 83,
Issue 7,
pp. 1935-1940,
04/01/1994
Copyright © 1994 by The American Society of Hematology
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