title: WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
abstract: The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/CXCR4 axis. We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.
authors.affiliation: Unité d'Immunologie Virale, Institut Pasteur, 75724 Paris, France.
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Bernard
authors.initials: B
authors.lastname: Lagane
authors.forename: José Luis
authors.initials: JL
authors.lastname: Pablos
authors.forename: Lysiane
authors.initials: L
authors.lastname: Laurent
authors.forename: Thierry
authors.initials: T
authors.lastname: Planchenault
authors.forename: Olivier
authors.initials: O
authors.lastname: Verola
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Delphine
authors.initials: D
authors.lastname: Kerob
authors.forename: Alain
authors.initials: A
authors.lastname: Dupuy
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Nicolas
authors.forename: Véronique
authors.initials: V
authors.lastname: Latger-Cannard
authors.forename: Danièle
authors.initials: D
authors.lastname: Bensoussan
authors.forename: Pierre
authors.initials: P
authors.lastname: Bordigoni
authors.forename: Françoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Virelizier
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000293:Adolescent; D000328:Adult; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000276:immunology; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology*; D018389:Codon, Nonsense; D005260:Female; D019204:GTP-Binding Proteins / Q000276:immunology; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D019655:Quantitative Trait, Heritable; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014860:Warts / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D018389:Codon, Nonsense; D019718:Receptors, CXCR4; D019204:GTP-Binding Proteins