Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.