title: Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis.
abstract: Mutations in more than 15 genes are now known to cause severe congenital neutropenia (SCN); however, the pathologic mechanisms of most genetic defects are not fully defined. Deficiency of G6PC3, a glucose-6-phosphatase, causes a rare multisystem syndrome with SCN first described in 2009. We identified a family with 2 children with homozygous G6PC3 G260R mutations, a loss of enzymatic function, and typical syndrome features with the exception that their bone marrow biopsy pathology revealed abundant neutrophils consistent with myelokathexis. This pathologic finding is a hallmark of another type of SCN, WHIM syndrome, which is caused by gain-of-function mutations in CXCR4, a chemokine receptor and known neutrophil bone marrow retention factor. We found markedly increased CXCR4 expression on neutrophils from both our G6PC3-deficient patients and G6pc3(-/-) mice. In both patients, granulocyte colony-stimulating factor treatment normalized CXCR4 expression and neutrophil counts. In G6pc3(-/-) mice, the specific CXCR4 antagonist AMD3100 rapidly reversed neutropenia. Thus, myelokathexis associated with abnormally high neutrophil CXCR4 expression may contribute to neutropenia in G6PC3 deficiency and responds well to granulocyte colony-stimulating factor.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. dmcdermott@niaid.nih.gov
authors.forename: David H
authors.initials: DH
authors.lastname: McDermott
authors.forename: Suk See
authors.initials: SS
authors.lastname: De Ravin
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Debra A Long
authors.initials: DA
authors.lastname: Priel
authors.forename: Pierre
authors.initials: P
authors.lastname: Noel
authors.forename: Clifford M
authors.initials: CM
authors.lastname: Takemoto
authors.forename: Teresa
authors.initials: T
authors.lastname: Ojode
authors.forename: Scott M
authors.initials: SM
authors.lastname: Paul
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Dunsmore
authors.forename: Dianne
authors.initials: D
authors.lastname: Hilligoss
authors.forename: Martha
authors.initials: M
authors.lastname: Marquesen
authors.forename: Jean
authors.initials: J
authors.lastname: Ulrick
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kuhns
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D005260:Female; D015870:Gene Expression; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D009503:Neutropenia / Q000151:congenital* / Q000201:enzymology / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics*; D013577:Syndrome
chemical_list: C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D005952:Glucose-6-Phosphatase; C492193:G6PC3 protein, human