A nonsense mutation (C-->T) truncating the CXC chemokine receptor 4 (CXCR4) C-terminal cytoplasmic tail domain occurred at nucleotide position 1000(R334X) of the CXCR4 gene in one allele of the patient was identified, and the person was diagnosed as having WHIM syndrome.
Thus, CXCR4 (L329fs) appears to be a de novo autosomal dominant frame-shift gain-of-function mutation that like other carboxy-terminus mutations causes WHIM syndrome.
Fewer patients with MYD88(L265P) and CXCR4(WHIM/FS or NS) vs MYD88(L265P)CXCR4(WT) presented with adenopathy (P < .01), further delineating differences in disease tropism based on CXCR4 status.
Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis).
Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome.
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.
Moreover, excessive neutrophil retention in hematopoietic tissue resulting from a constitutively active CXCR4 mutation in zebrafish warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is partially rescued by the inhibitory Rac2 mutation.
WHIM syndrome-associated CXCR4 truncation mutants lacking the S346/347 phosphosite and the recently identified E343KWHIM mutant displayed strongly impaired phosphorylation at S324/325 and S338/339 as well as reduced CXCL12-induced receptor internalization.
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.
We propose that decreased internalization of WHIM-associated mutated CXCR4 leads to prolongation/enhancement of signaling in response to SDF1 and that this may provide the biochemical basis for the autosomal dominant abnormalities of cell trafficking and function associated with WHIM syndrome.
WHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis.
These results suggest that WHIM-mutant CXCR4 may lead to spontaneous aberrant B-cell activation, via CXCL12-mediated costimulation, impairing B-cell survival and thus possibly contributing to the WHIM syndrome defects in adaptive immunity.
Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning.
Finding two patients with WHIM who do not have detectable mutations of CXCR4 but whose cells are hyperresponsive to CXCL12 raises the possibility that there is more than one genetic basis for WHIM.
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a genetic autoimmune disorder that results from gain-of-function mutations in the gene encoding chemokine receptor CXCR4.
An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia.