Journal
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
Volume 25, Issue 10, Pages 791-796Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00043426-200310000-00010
Keywords
neutropenia; Kostmann syndrome; filgrastim; granulocyte colony-stimulating factor receptor
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Funding
- NCI NIH HHS [R29CA7442] Funding Source: Medline
- NHLBI NIH HHS [K02 HL03794] Funding Source: Medline
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Severe chronic neutropenia (SCN) is characterized by a profound neutropenia, which mostly presents during the neonatal period. The precise genetic basis of SCN remains elusive. Acquired somatic mutations involving the carboxy-terminus of the G-CSF receptor (G-CSFR) have been found, often in association with myelodys-plastic syndrome. The authors describe a girl with SCN who did not respond to pharmacologic doses of filgrastim. Genetic analysis of bone marrow and germline cells revealed a 182-bp deletion in the extracellular domain of the G-CSFR. Co-precipitation studies showed an association between the wild-type and mutant G-CSFR, confirmed by their co-localization by confocal microscopy. Co-expression of the mutant receptor inhibited the wild-type response in Ba/F3 cells. These findings establish a novel constitutional defect in the G-CSFR that supports a partial dominant negative mechanism for receptor dysfunction in SCN.
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