title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
abstract: WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Haoqian
authors.initials: H
authors.lastname: Chen
authors.forename: Teresa
authors.initials: T
authors.lastname: Ojode
authors.forename: Xiangxi
authors.initials: X
authors.lastname: Gao
authors.forename: Sandra
authors.initials: S
authors.lastname: Anaya-O'Brien
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Turner
authors.forename: Jean
authors.initials: J
authors.lastname: Ulrick
authors.forename: Rosamma
authors.initials: R
authors.lastname: DeCastro
authors.forename: Corin
authors.initials: C
authors.lastname: Kelly
authors.forename: Adela R
authors.initials: AR
authors.lastname: Cardones
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Gold
authors.forename: Eugene I
authors.initials: EI
authors.lastname: Hwang
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wechsler
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: David H
authors.initials: DH
authors.lastname: McDermott
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D020014:K562 Cells; D007970:Leukopenia / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D017434:Protein Structure, Tertiary / Q000235:genetics; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000235:genetics*; D014860:Warts / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4