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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Amino Acid Substitution
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Animals
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Beclomethasone
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Child
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Chronic Disease
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Dimerization
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Female
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Genes, Dominant
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Germ-Line Mutation
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Granulocyte Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cell Transplantation
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Humans
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Leukocytosis / blood
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Leukocytosis / genetics*
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Male
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Middle Aged
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Models, Molecular
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Molecular Sequence Data
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Myeloproliferative Disorders / genetics
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Neutrophils* / drug effects
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Neutrophils* / pathology
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Point Mutation*
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Protein Structure, Tertiary
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Receptors, Colony-Stimulating Factor / chemistry
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Receptors, Colony-Stimulating Factor / genetics*
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Recombinant Proteins
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Transplantation, Heterologous
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Transplantation, Isogeneic
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Young Adult
Substances
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CSF3R protein, human
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Receptors, Colony-Stimulating Factor
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Recombinant Proteins
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Granulocyte Colony-Stimulating Factor
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Beclomethasone