Leukocytes from individuals with warts, hypogammaglobulinemia, infections, and 
myelokathexis (WHIM) syndrome, a rare immunodeficiency, and bearing a wild-type 
CXCR4 ORF (WHIM(WT)) display impaired CXCR4 internalization and desensitization 
upon exposure to CXCL12. The resulting enhanced CXCR4-dependent responses, 
including chemotaxis, probably impair leukocyte trafficking and account for the 
immunohematologic clinical manifestations of WHIM syndrome. We provided here 
evidence that GPCR kinase-3 (GRK3) specifically regulates CXCL12-promoted 
internalization and desensitization of CXCR4. GRK3-silenced control cells 
displayed altered CXCR4 attenuation and enhanced chemotaxis, as did WHIM(WT) 
cells. These findings identified GRK3 as a negative regulator of CXCL12-induced 
chemotaxis and as a candidate responsible for CXCR4 dysfunction in WHIM(WT) 
leukocytes. Consistent with this, we showed that GRK3 overexpression in both 
leukocytes and skin fibroblasts from 2 unrelated WHIM(WT) patients restored 
CXCL12-induced internalization and desensitization of CXCR4 and normalized 
chemotaxis. Moreover, we found in cells derived from one patient a profound and 
selective decrease in GRK3 products that probably resulted from defective mRNA 
synthesis. Taken together, these results have revealed a pivotal role for GRK3 
in regulating CXCR4 attenuation and have provided a mechanistic link between the 
GRK3 pathway and the CXCR4-related WHIM(WT) disorder.