title: Structural abnormalities in the G-CSF receptor in severe congenital neutropenia.
abstract: 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 increased 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 patients were cloned and sequenced. DNA mutations (point, deletion, frame-shift, and silent) were observed in 3 patients. In 2 of these, the DNA mutations resulted 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 loss of the transmembrane 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 that structural abnormalities in the G-CSF-R may be present in some SCN patients. They may not affect the binding of G-CSF to the receptor but may contribute to the pathogenesis of SCN through impaired signal transduction pathways of the mutant G-CSF-R.
authors.affiliation: James Ewing Laboratory of Developmental Hematopoiesis, Program of Cell Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Deshpande
authors.forename: P
authors.initials: P
authors.lastname: Lalezari
authors.forename: R G
authors.initials: RG
authors.lastname: Pergolizzi
authors.forename: M A
authors.initials: MA
authors.lastname: Moore
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000235:genetics / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor