title: Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia.
abstract: Severe congenital neutropenia (Kostmann syndrome) is characterized by profound absolute neutropenia and a maturation arrest of marrow progenitor cells at the promyelocyte-myelocyte stage. Marrow cells from such patients frequently display a reduced responsiveness to granulocyte-colony-stimulating factor (G-CSF). G-CSF binds to and activates a specific receptor which transduces signals critical for the proliferation and maturation of granulocytic progenitor cells. Here we report the identification of a somatic point mutation in one allele of the G-CSF receptor gene in a patient with severe congenital neutropenia. The mutation results in a cytoplasmic truncation of the receptor. When expressed in murine myeloid cells, the mutant receptor transduced a strong growth signal but, in contrast to the wild-type G-CSF receptor, was defective in maturation induction. The mutant receptor chain may act in a dominant negative manner to block granulocytic maturation.
authors.affiliation: Dr. Daniel den Hoed Cancer Center, Department of Hematology, Rotterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Dong
authors.forename: L H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: A M
authors.initials: AM
authors.lastname: Schelen
authors.forename: C A
authors.initials: CA
authors.lastname: Broeders
authors.forename: Y
authors.initials: Y
authors.lastname: Meijer
authors.forename: A J
authors.initials: AJ
authors.lastname: Veerman
authors.forename: I P
authors.initials: IP
authors.lastname: Touw
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
mesh_terms: D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009503:Neutropenia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017931:DNA Primers; D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor