Structural abnormalities in the G-CSF receptor in severe congenital neutropenia

Structural abnormalities in the cytoplasmic region of the G-CSF receptor (G -CSF-R) or defects in signal transduction pathways triggered by the G-CSF-R or both have been implicated in the development of neutropenia and increas ed prediposition to leukemia in patients with severe congenital neutropenia (SCN), To assess the structural integrity of the G-CSF-R in SCN patients, the transmembrane and cytoplasmic regions of the G-CSF-R from 5 SCN patient s were cloned and sequenced. DNA mutations (point, deletion, frame-shift, a nd silent) were observed in 3 patients, In 2 of these, the DNA mutations re sulted in altered G-CSF-R protein sequences, including additions of novel C -terminal sequences. Three of the 5 mutant receptor clones; lacked 115-121 amino acids in the cytoplasmic region, and 2 showed complete lass of the tr ansmembrane and cytoplasmic regions. Neutrophils from 1 patient expressing these mutant receptors, showed normal binding of radiolabeled G-CSF, G-CSF- R in 2 other patients with SCN showed no mutations. Our results indicate th at structural abnormalities in the G-CSF-R may be present in some SCN patie nts. They may not affect the binding of G-CSF to the receptor but may contr ibute to the pathogenesis of SCN through impaired signal transduction pathw ays of the mutant G-CSF-R.