The complex nature of CXCR4 mutations in WHIM syndrome

• Published in: Frontiers in immunology Vol. 15; p. 1406532
• Main Authors: Rodríguez-Frade, José Miguel, González-Granado, Luis Ignacio, Santiago, César A, Mellado, Mario
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 05.07.2024
• Subjects: Animals; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; CXCL12; CXCR4; Humans; Mutation; Primary Immunodeficiency Diseases - genetics; receptor conformations; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; Signal Transduction; signaling pathways; Thrombocytopenia - genetics; Warts - genetics; WHIM syndrome; β-arrestins; CXCR4; WHIM syndrome; β-arrestins; CXCL12; signaling pathways; receptor conformations
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1406532

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.