title: 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.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania, USA.
authors.forename: Srish
authors.initials: S
authors.lastname: Sinha
authors.forename: Quan Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Guillermo
authors.initials: G
authors.lastname: Romero
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002675:Child, Preschool; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008969:Molecular Sequence Data; D009503:Neutropenia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics*; D011994:Recombinant Proteins; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim