title: An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia.
abstract: 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.
authors.affiliation: Research Laboratory on Hematopoiesis and Normal and Leukemic Stem Cells, U790, Institut National de la Santé et de la Recherche Médicale, 94805 Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Le Couédic
authors.forename: Mayuka
authors.initials: M
authors.lastname: Nakatake
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Boulet
authors.forename: Miki
authors.initials: M
authors.lastname: Itaya
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000818:Animals; D001507:Beclomethasone; D002648:Child; D002908:Chronic Disease; D019281:Dimerization; D005260:Female; D005799:Genes, Dominant; D018095:Germ-Line Mutation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007964:Leukocytosis / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D016184:Receptors, Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous; D014185:Transplantation, Isogeneic; D055815:Young Adult
chemical_list: C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D001507:Beclomethasone