Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor.

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 myelodysplastic 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. Coexpression 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.