(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Leukocytosis

Topics: Adolescent; Adult; Aerosol Propellants; Asthma; Beclomethasone; Clinical Trials as Topic; Female; Humans; Hydrocortisone; Leukocytosis; Male; Methylprednisolone; Middle Aged

We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Substitution; Animals; Beclomethasone; Child; Chronic Disease; Dimerization; Female; Genes, Dominant; Germ-Line Mutation; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukocytosis; Male; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Models, Molecular; Molecular Sequence Data; Myeloproliferative Disorders; Neutrophils; Point Mutation; Protein Structure, Tertiary; Receptors, Colony-Stimulating Factor; Recombinant Proteins; Transplantation, Heterologous; Transplantation, Isogeneic; Young Adult