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Granulocyte colony-stimulating factor (G-CSF) production and G-CSF receptor
structure in patients with congenital neutropenia
SC Guba, CA Sartor, R Hutchinson, LA Boxer and SG Emerson
Department of Internal Medicine, University of Arkansas for Medical
Sciences, Little Rock.
Congenital neutropenia (Kostmann's syndrome [KS]) is an autosomal recessive
syndrome that is characterized by profound neutropenia, resulting in major
clinical infections and death. Since the neutropenia and symptoms in KS
improve in response to exogenous administration of granulocyte
colony-stimulating factor (G-CSF), we studied bone marrow cytokine (G-CSF,
granulocyte-macrophage CSF [GM-CSF], and interleukin- 6) production under
both basal and stimulated conditions. No differences in G-CSF, GM-CSF, or
IL-6 gene expression were found in bone marrow stromal cells between normal
controls and KS patients, and all three cytokines were detected by
enzyme-linked immunosorbent assay (ELISA) in medium conditioned by bone
marrow stromal cells from normal donors and patients with KS. Each KS
patient tested had detectable, functional G-CSF in their own serum before
exogenous G-CSF administration. Since G-CSF production appeared normal in
KS patients, we then asked whether we could detect structural defects in
the signaling portion of G-CSF receptor genes. Polymerase chain reaction
(PCR) amplification of the G-CSF receptor transmembrane region alone, and
of the transmembrane plus cytosolic portions of the receptor, yielded the
size products predicted from the sequences of the normal G- CSF receptor.
Single-strand conformational polymorphism (SSCP) analysis of G-CSF receptor
PCR products demonstrated no variance in structural conformation between KS
patients and normal subjects. These results demonstrate that bone marrow
stromal cells in patients with KS secrete normal concentrations of
functional G-CSF and suggest that the neutropenia in KS patients is caused
by an inability of neutrophilic progenitor and precursor cells to respond
to normal, physiologic levels of G-CSF. Such a defect, clinically
responsive to pharmacologic doses of G-CSF, might be caused by defects in
the post-G-CSF receptor signal transduction pathway.
Volume 83,
Issue 6,
pp. 1486-1492,
03/15/1994
Copyright © 1994 by The American Society of Hematology
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