Identification of a Nonsense Mutation in the Granulocyte-Colony-Stimulating Factor Receptor in Severe Congenital Neutropenia

• Published in: Proceedings of the National Academy of Sciences - PNAS 1994-05, Vol.91 (10), p.4480-4484
• Main Authors: Dong, Fan, Hoefsloot, Lies H., Schelen, Anita M., Lianne C. A. M. Broeders, Meijer, Yolande, Anjo J. P. Veerman, Touw, Ivo P., Lowenberg, Bob
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal; Antigens, CD - analysis; B lymphocytes; Base Sequence; Bone marrow; Bone Marrow - pathology; Cell lines; Child; Colony-Forming Units Assay; Complementary DNA; congenital defects; DNA Primers; Erythroid cells; Genetic mutation; granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - pharmacology; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - pathology; Humans; identification; Interleukin-3 - pharmacology; Macrophage Colony-Stimulating Factor - pharmacology; Male; man; Molecular Sequence Data; mutation; Myeloid cells; neutropenia; Neutropenia - blood; Neutropenia - genetics; Neutropenia - pathology; Neutrophils; Point Mutation; Polymerase Chain Reaction - methods; Receptors; Receptors, Granulocyte Colony-Stimulating Factor - biosynthesis; Receptors, Granulocyte Colony-Stimulating Factor - genetics; Recombinant Proteins - pharmacology; T lymphocytes; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.10.4480

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.