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.
These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.
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 mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.
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.
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.
Using S1P5(-/-) mice and a new knockin mouse model in which CXCR4 cannot be desensitized (a mouse model of warts, hypogammaglobulinemia, infections, and myelokathexis [WHIM] syndrome), we demonstrate that NK-cell exit from the BM requires both CXCR4 desensitization and S1P5 engagement.
Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis).
As a result we can expect to identify markers of the WHIM syndrome, as well as other disorders with WHIM-like features that are associated with dysfunctions of the CXCL12/CXCR4 axis.
The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals.
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.
Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor.
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.
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.
Potential involvement of this novel motif in cancer metastasis and other CXCR4-associated disorders such as warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome is discussed.
Importantly, the involvement of CXCR4 in cancer metastasis and WHIM syndrome appears to be due to dysregulation of the receptor leading to enhanced signaling.
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.
We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.
We propose that the sustained CXCR4 activity in patient cells accounts for the immune-hematologic clinical manifestations and the profusion of warts characteristic of the WHIM syndrome.
The mutated gene may result in production of the mutant CXCR4 protein causing abnormal apoptosis and migratory function, which are thought to be related to the cause of chronic neutropenia in WHIM syndrome.