The C-terminal mutations in CXCR4 that occur in WHIM syndrome appear to disrupt the normal mechanisms involved in regulating CXCR4 function, which include agonist-dependent phosphorylation of the receptor by GRKs and protein kinase C (PKC), desensitization mediated by β-arrestin binding, ubiquitination by the E3 ubiquitin ligase AIP4, endocytosis, and sorting to lysosomes where the receptor is degraded (14, 23, 24, 25, 26). Here, CXCR4 is linked to WHIM syndrome.