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An inherited defect of neutrophil motility and microfilamentous
cytoskeleton associated with abnormalities in 47-Kd and 89-Kd proteins
TD Coates, JC Torkildson, M Torres, JA Church and TH Howard
Department of Pediatrics, University of Southern California School of
Medicine, Childrens Hospital Los Angeles, 90027.
A 2-month-old male Tongan infant presented with fever, severe skin and
mucosal infections, hepatosplenomegaly, thrombocytopenia, and normal
neutrophil counts. While polymorphonuclear neutrophil (PMN) morphology was
normal, several neutrophil motile functions were found to be altered in the
patient. Furthermore, two siblings had died in infancy with a similar
clinical picture, raising the possibility of an inherited neutrophil
defect. Random migration and chemotaxis, assessed by the under agarose
method, were profoundly impaired. Actin polymerization, as measured by flow
cytometry of N-(7-nitrobenz-2-oxa- 1,3-diazol-4-yl)phallacidin
(NBD-phallacidin)-stained PMNs, showed lower basal F-actin and a 1.75-fold
increase in response to 10(-7) mol/L formyl-methionyl-leucyl-phenylalanine
(FMLP) compared with a 4.51- fold increase in control. Microscopic
examination of NBD-phallacidin- stained PMN spread on glass showed
decreased area of spreading and F- actin-rich filamentous projections
distinct from control. The early phase of FMLP-induced right angle light
scattering was absent, similar to the effect caused by cytochalasin-B (CB),
an inhibitor of actin polymerization. Accordingly, FMLP induced secretion
of elastase without the addition of CB. Staphylococcus aureus killing was
50% of control whereas superoxide production response to FMLP and surface
expression of CD11b were greater than twice normal. Partial defects in
actin polymerization and scatter were seen in the parents and release of
elastase, in the absence of CB, was also increased in both parents. Sodium
dodecyl sulfate-polyacrylamide electrophoresis of whole cell proteins from
the patient showed a marked decrease in an 89-Kd protein (8% of control)
and a marked increase in a 47-Kd protein (4.2-fold). Both mother and father
had decreased 89-Kd (77% and 42% of control) and increased 47-Kd proteins
(2- and 3.4-fold), although neither had recurrent infections or chemotactic
defects. These studies describe a new inherited actin dysfunction syndrome
associated with severe propensity to fungal infection and draw attention to
the proteins of apparent molecular weights of 89 Kd and 47 Kd, which may be
of great importance in the regulation of actin polymerization in human
PMNs.
Volume 78,
Issue 5,
pp. 1338-1346,
09/01/1991
Copyright © 1991 by The American Society of Hematology
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