An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia.
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.
Plo
Isabelle
I
Research Laboratory on Hematopoiesis and Normal and Leukemic Stem Cells, U790, Institut National de la Santé et de la Recherche Médicale, 94805 Villejuif, France.
Zhang
Yanyan
Y
Le Couédic
Jean-Pierre
JP
Nakatake
Mayuka
M
Boulet
Jean-Michel
JM
Itaya
Miki
M
Smith
Steven O
SO
Debili
Najet
N
Constantinescu
Stefan N
SN
Vainchenker
William
W
Louache
Fawzia
F
de Botton
Stéphane
S
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
C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D001507:Beclomethasone