Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.
Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.
Person
Richard E
RE
Department of Pathology, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195, USA.
Li
Feng-Qian
FQ
Duan
Zhijun
Z
Benson
Kathleen F
KF
Wechsler
Jeremy
J
Papadaki
Helen A
HA
Eliopoulos
George
G
Kaufman
Christina
C
Bertolone
Salvatore J
SJ
Nakamoto
Betty
B
Papayannopoulou
Thalia
T
Grimes
H Leighton
HL
Horwitz
Marshall
M
D000328:Adult; D000368:Aged; D002675:Child, Preschool; D002875:Chromosomes / Q000276:immunology; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000235:genetics*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D009503:Neutropenia / Q000097:blood / Q000209:etiology / Q000235:genetics*; D009504:Neutrophils / Q000201:enzymology; D010375:Pedigree; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D008156:Luciferases; D019272:Leukocyte Elastase