WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named 
because it is characterized by warts, hypogammaglobulinemia, infections, and 
myelokathexis (defective neutrophil egress from the BM). Gain-of-function 
mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 
amino acids cause WHIM syndrome. We have identified a family with autosomal 
dominant inheritance of WHIM syndrome that is caused by a missense mutation in 
CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal 
domain, a region responsible for negative regulation of the receptor. 
Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM 
syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in 
calcium flux and chemotaxis assays relative to wild-type CXCR4; however, 
CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation 
from the cell surface. Therefore, in addition to truncating mutations in the 
C-terminal domain of CXCR4, WHIM syndrome may be caused by a single 
charge-changing amino acid substitution in this domain, E343K, that results in 
increased receptor signaling.