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: Karl Balabanian, Bernard Lagane, José Luis Pablos, Lysiane Laurent, Thierry Planchenault, Olivier Verola, Celeste Lebbe, Delphine Kerob, Alain Dupuy, Olivier Hermine, Jean-François Nicolas, Véronique Latger-Cannard, Danièle Bensoussan, Pierre Bordigoni, Françoise Baleux, Françoise Le Deist, Jean-Louis Virelizier, Fernando Arenzana-Seisdedos, Françoise Bachelerie
• Journal: Blood (Blood) Vol. 105 Issue 6 Pg. 2449-57 (Mar 15 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15536153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines, CC
• Chemokines, CXC
• Codon, Nonsense
• Receptors, CXCR4
• GTP-Binding Proteins

Topics

• Adolescent
• Adult
• Chemokine CXCL12
• Chemokines, CC (immunology)
• Chemokines, CXC (genetics, immunology)
• Codon, Nonsense
• Female
• GTP-Binding Proteins (immunology)
• Genetic Diseases, Inborn (genetics, immunology, pathology)
• Heterozygote
• Humans
• Immunologic Deficiency Syndromes (genetics, immunology, pathology)
• Lymphocytes (immunology, pathology)
• Male
• Neutrophils (immunology, pathology)
• Open Reading Frames (genetics, immunology)
• Pedigree
• Quantitative Trait, Heritable
• Receptors, CXCR4 (genetics, immunology)
• Signal Transduction (genetics, immunology)
• Warts (genetics, immunology, pathology)