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.

*Point Mutation, Antibodies, Monoclonal, Antigens, CD/analysis, Base Sequence, Bone Marrow/pathology, Child, Colony-Forming Units Assay, DNA Primers, Granulocyte Colony-Stimulating Factor/*pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology, Hematopoietic Stem Cells/drug effects/*pathology, Humans, Interleukin-3/pharmacology, Macrophage Colony-Stimulating Factor/pharmacology, Male, Molecular Sequence Data, Neutropenia/blood/*genetics/pathology, Polymerase Chain Reaction/methods, Receptors, Granulocyte Colony-Stimulating Factor/biosynthesis/*genetics, Recombinant Proteins/pharmacology, Transfection
Proceedings of the National Academy of Sciences of the United States of America
Erasmus MC: University Medical Center Rotterdam

Dong, F, Hoefsloot, E.H, Schelen, A.M, Broeders, C.A, Meijer, Y, Veerman, A.J, … Löwenberg, B. (1994). Identification of a nonsense mutation in the granulocyte-colony-stimulating factor receptor in severe congenital neutropenia. Proceedings of the National Academy of Sciences of the United States of America. Retrieved from