* 162643

CHEMOKINE, CXC MOTIF, RECEPTOR 4; CXCR4


Alternative titles; symbols

NEUROPEPTIDE Y RECEPTOR Y3; NPY3R
FUSIN
D2S201E
LEUKOCYTE-DERIVED SEVEN-TRANSMEMBRANE-DOMAIN RECEPTOR; LESTR
SEVEN-TRANSMEMBRANE-SEGMENT RECEPTOR, SPLEEN
HM89
LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 3; LAP3
LPS-ASSOCIATED PROTEIN 3


HGNC Approved Gene Symbol: CXCR4

Cytogenetic location: 2q22.1     Genomic coordinates (GRCh38): 2:136,114,349-136,118,149 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q22.1 Myelokathexis, isolated 193670 AD 3
WHIM syndrome 1 193670 AD 3

TEXT

Cloning and Expression

Several receptors for neuropeptide Y (NPY; 162640) have been demonstrated and shown to differ in pharmacologic characteristics, tissue distribution, and structure of the encoding genes; see the NPY Y1 receptor (NPY1R; 162641) and the NPY Y2 receptor (NPY2R; 162642). Herzog et al. (1993) cloned, sequenced, and mapped the human homolog of a proposed bovine NPY Y3 receptor reported by Rimland et al. (1991). The human cDNA clone was derived from a human lung cDNA library. The 1,670-bp sequence predicts a single open reading frame (ORF) of 352 amino acids, with 92% amino acid identity to the reported bovine sequence. The amino acid sequence shares features common to many other G protein-coupled receptors, including the 7-transmembrane regions and putative glycosylation and phosphorylation sites. The receptor shows 36% identity to the interleukin-8 receptor (IL8RA; 146929), which is located on chromosome 2, and to the angiotensin II receptor (AGTR1; 106165), but only 21% identity to the NPY Y1 receptor.

The recruitment of leukocytes to inflamed tissues involves interleukin-8 (IL8; 146930) and several related chemotactic cytokines that attract and activate leukocytes. Loetscher et al. (1994) noted that these proteins are similar in size, have marked sequence similarities, and are characterized by 4 conserved cysteines that form 2 essential disulfide bonds. Two subfamilies are distinguished according to the arrangement of the first 2 cysteines, which are either adjacent (CC subfamily) or separated by one amino acid (CXC subfamily). The CXC cytokines activate primarily neutrophil leukocytes, while CC cytokines act on monocytes, basophils, and eosinophils. These chemotactic agonists act via 7-transmembrane domain, G protein-coupled receptors, e.g., the 2 interleukin-8 receptors, IL8RA and IL8RB (146928). Chemotactic cytokines of the CC subfamily do not bind to IL8 receptors. Loetscher et al. (1994) isolated from a human blood monocyte cDNA library a cDNA clone encoding a protein of 352 amino acids, corresponding to a receptor of the 7-transmembrane domain, G protein-coupled type. They referred to the gene and the deduced protein as LESTR for 'leukocyte-derived seven-transmembrane domain receptor.' It shows 92.6% identity with a bovine neuropeptide Y receptor. In the monocyte library, LESTR cDNA fragments were about 20 times as frequent as cDNA coding for IL8RA and IL8RB, and much higher levels of mRNA specific for LESTR than for IL8R were found in human blood neutrophils and lymphocytes. Although the ligand for LESTR could not be identified among a large number of chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to IL8RA and IL8RB suggested to Loetscher et al. (1994) that LESTR may function in the activation of inflammatory cells.

The human CD4 molecule (186940) acts as the primary receptor for the human immunodeficiency virus type 1 (HIV-1), but CD4 supports viral entry into cells only when it is expressed on specific human cell types (Clapham et al., 1991). Weiner et al. (1991) and Dragic and Alizon (1993) presented evidence that the restriction of HIV-1 infection to certain human cell types is the result of a specific cofactor, encoded in the human genome, which is required for cell virus membrane fusion. Feng et al. (1996) undertook the isolation and characterization of the putative human HIV-1 fusion cofactor using an approach that made no assumptions about the mode of action of the cofactor other than that the cofactor would allow a CD4-expressing nonhuman cell to undergo viral fusion. They transfected CD4-expressing NIH 3T3 cells with a HeLa cell cDNA library and then incubated the transfected cells with an NIH 3T3 cell line expressing the HIV-1 Env gene (which is required by HIV-1 for fusion); transfected CD4+ cells that fused with Env-expressing cells could be distinguished by utilizing a lacZ biochemical marker specific to such fusion products. Feng et al. (1996) isolated a 1.7-kb human cDNA clone that allowed the CD4-expressing NIH 3T3 cells to undergo fusion. The cDNA contained a 352-codon ORF whose predicted amino acid sequence has 7 predicted transmembrane segments and resembles that of the G protein-coupled receptor superfamily. The predicted molecular weight of the protein is 39,745 Da and its primary sequence includes 2 potential N-linked glycosylation sites. The cDNA had in fact been cloned previously by Federsppiel et al. (1993) from a human fetal spleen cDNA library and was designated D2S201E. The predicted protein has 37% amino acid identity with the interleukin-8 receptor and is 93% identical to that of a cDNA isolated from bovine locus ceruleus, which apparently encodes a neuropeptide Y receptor.


Gene Structure

Wegner et al. (1998) determined the genomic organization and promoter function of CXCR4. The gene contains 2 exons of 103 and 1,563 bp separated by an intron of 2,132 bp between codons 5 and 6 of the coding sequence. Sequence analysis predicted that the promoter region includes a TATA box, a nuclear respiratory factor-1 (NRF1; 600879) site, and 2 GC boxes. Deletion of the NRF1 site abolished CXCR4 promoter activity. Electrophoretic mobility shift assay (EMSA) experiments demonstrated that the transcriptional regulator NRF1 binds to the NRF1 site in the CXCR4 promoter. Caruz et al. (1998) also reported the genomic structure of CXCR4.


Mapping

By PCR analysis of human/hamster hybrid cell DNA, Herzog et al. (1993) showed that the NPY3R gene is located on human chromosome 2.

Federsppiel et al. (1993) localized D2S201E, the expressed segment encoding fusin, to chromosome 2q21 by isotopic in situ hybridization. This finding was corroborated by the mapping of the NPY3R gene to chromosome 2 by Herzog et al. (1993).


Biochemical Features

Crystal Structure

Wu et al. (2010) reported 5 independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5- to 3.2-angstrom resolution. All structures revealed a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. Wu et al. (2010) concluded that these structures provided new clues about the interactions between CXCR4 and its natural ligand CXCL12 (600835) and with the HIV-1 glycoprotein gp120.

Qin et al. (2015) reported the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1-angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic 2-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.


Gene Function

Herzog et al. (1993) reported that NPY and a number of other ligands failed to induce any change in cytosolic calcium levels in transfected cells, suggesting that this clone represented a novel neuropeptide receptor. Jazin et al. (1993) independently found that the Y3 receptor does not respond to NPY.

Feng et al. (1996) showed that transient expression of the CXCR4 gene (called 'fusin' by the authors) allowed nonhuman cells coexpressing recombinant CD4 to undergo Env-CD4-mediated cell fusion and productive HIV-1 infection. The authors used Northern analysis to show that fusin mRNA levels correlated with HIV-1 permissiveness in diverse human cell types; Federsppiel et al. (1993) had previously found that D2S201E was expressed in a variety of tissues, including brain and tissues of hemopoietic origin. Feng et al. (1996) also showed that anti-fusin antibodies strongly inhibited HIV-1 infection of normal human CD4+ target cells. The authors commented that the identification of fusin as a fusion cofactor for T-cell line-tropic HIV-1 isolates provided a new means of elucidating the mechanism of HIV-1 infection and suggested that production of an effective small-animal model of HIV infection might be possible.

Bleul et al. (1996) and Oberlin et al. (1996) reported that stromal cell-derived factor-1 (SDF1; 600835), also known as CXCL12 and PBSF, is a ligand for this receptor, which they referred to as CXCR4. Both groups found that SDF1 is a potent inhibitor in vitro of infection by lymphocyte-tropic HIV-1 strains. Oberlin et al. (1996) showed that the CC chemokines MIP-1-alpha (182283), MIP-1-beta (182284), and RANTES (187011), which inhibit monocyte-tropic HIV-1 infection via the CC chemokine receptor CMKBR5 (CCR5; 601373), were inactive against lymphocyte-tropic HIV-1 strains. Conversely, Bleul et al. (1996) showed that SDF1 does not inhibit CMKBR5-mediated infection by macrophage-tropic and dual-tropic HIV-1.

CCR5 is the major macrophage-tropic coreceptor for HIV-1, whereas CXCR4 serves the counterpart function for T cell-tropic viruses. Xiao et al. (2000) provided an explanation for the mystery of why only R5-HIV-1 is initially detected in new seroconvertors who are exposed to R5 and X4 viruses. Indeed, X4 virus emerges in a minority of patients and only in the late stages of disease, suggesting that early negative selection against HIV-1-CXCR4 interaction may exist. Xiao et al. (2000) reported that the HIV-1 Tat protein (HTATIP; 601409), which is secreted from virus-infected cells, is a CXCR4-specific antagonist. Soluble Tat selectively inhibited the entry and replication of X4, but not R5, virus in peripheral blood mononuclear cells. The authors proposed that one functional consequence of secreted Tat is to select against X4 viruses, thereby influencing the early in vivo course of HIV-1 disease.

Peled et al. (1999) demonstrated that SDF1 and its receptor CXCR4 are critical for murine bone marrow engraftment by human SCID repopulating stem cells. Treatment of human cells with anti-CXCR antibodies prevented engraftment. They further demonstrated that CD34(+)CD38(-/low) cells could be converted to CD34(+)CD38(-/low)CXCR4(+) stem cells by pretreatment with IL6 (147620) and stem cell factor (KITLG; 184745), which increased CXCR4 expression. This pretreatment potentiated migration to SDF1 and engraftment in primary and secondary transplanted mice.

Breast cancer metastasis occurs in a distinct pattern involving the regional lymph nodes, bone marrow, lung, and liver, but rarely other organs. By real-time quantitative PCR, immunohistochemistry, and flow cytometric analysis, Muller et al. (2001) found that CXCR4 is highly expressed in primary and metastatic human breast cancer cells but is undetectable in normal mammary tissue, whereas CCR7 (600242) is significantly expressed in normal tissue and is upregulated in breast cancer cells. Quantitative PCR analysis also detected peak expression levels of the CXCR4 ligand, CXCL12 (SDF1) in lymph nodes, lung, liver, and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant in lymph nodes, the organs to which primary breast cancer cells preferentially migrate. Analysis of malignant melanomas determined that in addition to CXCR4 and CCR7, these tumors also had high levels of CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific chemokine involved in the homing of memory T cells into the skin. Flow cytometric analysis and confocal laser microscopy demonstrated that either CXCL12 or CCL21 induces high levels of F-actin polymerization and pseudopod formation in breast cancer cells. These chemokines, as well as lung and liver extracts, also induce directional migration of breast cancer cells in vitro, which can be blocked by antibodies to CXCR4 or CCL21. Histologic and quantitative PCR analyses showed that metastasis of intravenously or orthotopically injected breast cancer cells could be significantly decreased in SCID mice by treatment with anti-CXCR4 antibodies. Muller et al. (2001) proposed that the nonrandom expression of chemokine receptors in breast cancer and malignant melanoma, and probably in other tumor types, indicates that small molecule antagonists of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to interfere with tumor progression and metastasis in tumor patients.

Chan et al. (2003) investigated the expression of chemokines and chemokine receptors in eyes with primary intraocular B-cell lymphoma (PIOL). All 3 PIOL eyes showed similar pathology, with typical diffuse large B-lymphoma cells between the retinal pigment epithelium (RPE) and Bruch membrane. The eyes also showed a similar chemokine profile with the expression of CXCR4 and CXCR5 (BLR1; 601613) in the lymphoma cells. CXCL13 (605149) and CXCL12 transcripts were found only in the RPE and not in the malignant cells. No chemokine expression was detected on the RPE cells of a normal control eye. Since chemokines and chemokine receptors selective for B cells were identified in RPE and malignant B cells in eyes with PIOL, inhibition of B-cell chemoattractants might be a future strategy for the treatment of PIOL.

Liotta (2001) reviewed the theories explaining the bias of metastases toward certain organs and addressed questions raised by the work of Muller et al. (2001).

CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, Triantafilou et al. (2001) identified 4 diverse proteins, heat-shock cognate protein (HSPA8; 600816), HSP90A (HSPCA; 140571), chemokine receptor CXCR4, and growth/differentiation factor-5 (GDF5; 601146), on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. Triantafilou et al. (2001) proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens.

Levesque et al. (2003) demonstrated that the mobilization of hematopoietic progenitor cells (HPCs) by granulocyte colony-stimulating factor (GCSF; 138970) or cyclophosphamide was due to the disruption of the CXCR4/CXCL12 chemotactic pathway. The mobilization of HPCs coincided in vivo with the cleavage of the N terminus of the chemokine receptor CXCR4 found on HPCs. This resulted in the loss of chemotactic response of the HPCs to the CXCR4 ligand, CXCL12. The concentration of CXCL12 was also decreased in vivo in the bone marrow of mobilized mice, and this decrease coincided with the accumulation of serine proteases capable of direct cleavage and inactivation of CXCL12. As both CXCL12 and CXCR4 are essential for the homing and retention of HPCs in the bone marrow, the proteolytic degradation of CXCL12 and CXCR4 may represent a critical step in the mobilization of HPCs into the peripheral blood by GCSF or cyclophosphamide.

Ichiyama et al. (2003) showed that a low molecular mass nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic HIV-1 in cultured cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXCR4 receptor but not via CCR5. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography-mass spectrometry. Thus, KRH-1636 seemed to be a promising agent for the treatment of HIV-1 infection.

Hwang et al. (2003) characterized the expression of CXCR4 and analyzed its functions in ARO cells, a human anaplastic thyroid carcinoma (ATC) cell line. Fluorescence-activated cell sorting (FACS) analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA (both human thyroid carcinoma cell lines), and normal thyroid cells did not express membrane CXCR4, as determined by FACS. The authors concluded that these findings suggested that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.

Staller et al. (2003) demonstrated that the von Hippel-Lindau tumor suppressor protein (VHL; see 608537) negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF1-alpha; 603348) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. Staller et al. (2003) concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

Marchese et al. (2003) determined that AIP4 colocalized with CXCR4 at the plasma membrane in transfected HEK293 cells and that it colocalized with HRS (604375) on endosomes in transfected HeLa cells. AIP4, HRS, and a vacuole sorting protein, VPS4, were required for targeting CXCR4 to the degradative pathway.

The germinal center (GC) is organized into dark and light zones. B cells in the dark zone, called centroblasts, undergo rapid proliferation and somatic hypermutation of their antibody variable genes. Centroblasts then become smaller, nondividing centrocytes and undergo selection in the light zone based on the affinity of their surface antibody for the inducing antigen. The light zone also contains helper T cells and follicular dendritic cells that sequester antigen. Failure to differentiate results in centrocyte apoptosis, whereas centrocytes that bind antigen and receive T-cell help emigrate from the GC as long-lived plasma cells or memory B cells. Some centrocytes may also return to the dark zone for further proliferation and mutation. Using genetic and pharmacologic approaches, Allen et al. (2004) showed that CXCR4 was essential for GC dark and light zone segregation. In the presence of the antiapoptotic BCL2 (151430), B cells had robust chemotactic responses to the CXCR4 ligand, CXCL12, as well as to CXCL13, the ligand for CXCR5. CXCL12 was more abundant in the dark zone, and CXCR4 was more abundant on centroblasts than centrocytes. In contrast, CXCR5 helped direct cells to the CXCL13-positive light zone, but was not essential for segregation of the 2 zones. CXCL13 and CXCR5 were required for correct positioning of the light zone. Allen et al. (2004) concluded that these chemokines and their receptors are critical for movement of cells to different parts of the GC and for creating the distinct histologic appearance of the GC. They suggested that GC organization is likely to be disrupted in individuals with WHIM syndrome (WHIMS; 193670) resulting from C-terminal truncation mutations in CXCR4.

Using immunofluorescence microscopy, Yeaman et al. (2004) examined expression of the HIV receptors CD4 and galactosylceramide (see GALC; 606890) and the HIV coreceptors CXCR4 and CCR5 in ectocervical specimens from hysterectomy patients with benign diseases. CD4 expression was detected on epithelial cells at early and midproliferative stages of the menstrual cycle, whereas galactosylceramide expression was uniform in all stages of the menstrual cycle. CXCR4 was not detected on ectocervical epithelial cells, whereas CCR5 was expressed on ectocervical epithelial cells at all stages of the menstrual cycle. CD4-positive leukocytes were present in the basal and precornified layers of squamous epithelium during early and midproliferative phases of the menstrual cycle, but were absent in later proliferative phases and the secretory phase; the presence of CD4-positive leukocytes was not related to inflammation. Yeaman et al. (2004) concluded that HIV infection of the ectocervix most likely occurs through galactosylceramide and CCR5.

Feng et al. (2006) found that beta-defensin-3 (HBD3, or DEFB103A; 606611) not only blocked HIV-1 replication via direct interaction with virions and modulation of the CXCR4 coreceptor, but it also competed with the CXCR4 ligand, SDF1, and promoted internalization of CXCR4 without inducing calcium flux, ERK (see MAPK3; 601795) phosphorylation, or chemotaxis. HBD3 had no effect on other G protein-coupled receptors (e.g., CCR5). Feng et al. (2006) proposed that HBD3 or its derivatives may have potential for HIV and/or immunoregulatory therapy.

Jin et al. (2006) found that hematopoietic cytokines, particularly Kitlg and Tpo (THPO; 600044), induced release of Sdf1 from mouse platelets and enhanced neovascularization of ischemic hindlimbs through mobilization of Cxcr4-positive/Vegfr (KDR; 191306)-positive hematopoietic progenitors termed hemangiocytes. Revascularization was profoundly impaired in Mmp9 (120361)-deficient mice, which have impaired release of soluble Kitlg from membrane Kitlg, as well as Tpo-deficient mice and Tpor (MPL; 159530)-deficient mice. Transplantation of Cxcr4-positive/Vegfr-positive hemangiocytes restored revascularization in Mmp9-deficient mice. Jin et al. (2006) concluded that hematopoietic cytokines, through graded deployment of platelet-derived SDF1, support mobilization and recruitment of CXCR4-positive/VEGFR-positive hemangiocytes.

Vasyutina et al. (2005) showed that migrating muscle progenitors express Cxcr4 and noted that the Cxcr4 ligand Sdf1 is expressed in limb and branchial arch mesenchyme, i.e., along the routes and at the targets of migratory cells. Ectopic application of Sdf1 in chick limb attracted muscle progenitor cells. In Cxcr4 mutant mice, the number of muscle progenitors that colonized the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of muscle progenitor cells was accompanied by increased apoptosis, indicating that Cxcr4 signals provide not only attractive cues, but also control survival. Vasyutina et al. (2005) further found that muscle progenitors of Cxcr4/Gab1 (604439) double mutants did not reach the anlage of the tongue, suggesting that these proteins interact during progenitor cell migration.

Using immunohistochemistry, Lieberam et al. (2005) showed that mouse ventral motor neurons (vMNs) transiently expressed Cxcr4 as they followed their ventral trajectory, whereas Cxcl12 was expressed by mesenchymal cells surrounding the ventral neural tube. In mice lacking Cxcr4 or Cxcl12, vMNs adopted a dorsal motor neuron (dMN)-like trajectory. Axons of Cxcr4-deficient vMNs frequently invaded sensory ganglia, a characteristic dMN trajectory. Lieberam et al. (2005) concluded that a G protein-coupled receptor signaling system controls the precision of initial motor axon trajectories and that CXCR4 is a crucial effector of the transcriptional pathway specifying vMN connectivity.

By studying brains of mice and humans with West Nile virus (WNV; see 610379) encephalitis, McCandless et al. (2008) found downregulation of the beta isoform of CXCL12, but not the alpha isoform, as well as a decline of perivascular T cells and an increase in parenchymal T cells. Treatment with a continuously administered Cxcr4 antagonist increased the survival of WNV-infected mice and eventually caused a reduction in WNV burden in the brain. Cxcr4 antagonism also enhanced T-cell penetration in the brain after WNV encephalitis, increased virus-specific Cd8-positive T-cell interaction with infected cells, and decreased glial cell activation in infected brains. McCandless et al. (2008) proposed that targeting CXCR4 may allow enhanced CD8-positive T-cell infiltration without increased immunopathology in viral infections of the central nervous system.

Ding et al. (2014) combined an inducible endothelial cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury to show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The profibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor ID1 (600349), deploying proregenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive Fgfr1 (136350) signaling in liver sinusoidal endothelial cells counterbalanced Cxcr7-dependent proregenerative response and augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin (125660)-positive hepatic stellate-like cells and enforcing a profibrotic vascular niche. Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice restored the proregenerative pathway and prevented Fgfr1-mediated maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Ding et al. (2014) demonstrated that in response to liver injury, differential recruitment of proregenerative CXCR7-ID1 versus profibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis.


Molecular Genetics

WHIM syndrome-1 (WHIMS1; 193670) is an autosomal dominant immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis (kathexis = retention). The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be particularly important in the natural control of this infection. By genomewide scan, Hernandez et al. (2003) mapped the gene mutant in WHIMS1 to a region of roughly 12 cM on 2q21, and by screening the most attractive positional candidate in this region, CXCR4, they identified truncating mutations in the cytoplasmic tail domain of the CXCR4 gene (162643.0001-162643.0003) in 6 unrelated families with WHIMS1.

Balabanian et al. (2005) identified a heterozygous nonsense mutation in the CXCR4 gene (S338X; 162643.0004) in 2 sibs with WHIMS1.

In 8 patients from 3 unrelated families with WHIMS1, Beaussant Cohen et al. (2012) identified heterozygous nonsense or frameshift mutations in the CXCR4 gene (see, e.g., 162643.0001, 162643.0004, 162643.0005). The distal truncations of the C-tail of the protein were predicted to remove potential phosphorylation sites involved in the attenuation process. The findings were consistent with a gain-of-function effect. Family 4 had previously been reported by Balabanian et al. (2005).


Nomenclature

Depending on what properties were being studied, this molecule has been called neuropeptide Y receptor Y3, fusin, and leukocyte-derived 7-transmembrane-domain receptor, among various designations.


Animal Model

Vascularization of organs generally occurs by remodeling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required for early vascular systems, many of which are receptor tyrosine kinases and their ligands, are revealed by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis are not identified by this approach. CXCR4 is responsible for B-cell lymphopoiesis, bone marrow myelopoiesis, and cardiac ventricular septum formation. CXCR4 also functions as a coreceptor for HIV-1 and is a receptor for the CXC chemokine PBSF/SDF1 (600835). Tachibana et al. (1998) showed that CXCR4 is expressed in developing vascular endothelial cells. Tachibana et al. (1998) found that mice lacking either CXCR4 or PBSF/SDF1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, hematopoiesis and cardiogenesis, like mice lacking PBSF/SDF1, indicating that CXCR4 is a primary physiologic receptor for PBSF/SDF1. Tachibana et al. (1998) concluded that PBSF/SDF1 and CXCR4 define a new signaling system for organ vascularization.

Zou et al. (1998) pointed out that CXCR4 is broadly expressed in cells of both the immune and the central nervous systems and can mediate migration of resting leukocytes and hematopoietic progenitors in response to its ligand, SDF1. They showed that mice lacking CXCR4 exhibit hematopoietic and cardiac defects identical to those of SDF1-deficient mice (Nagasawa et al., 1996), indicating that CXCR4 may be the only receptor for SDF1. Furthermore, fetal cerebellar development in mutant animals was markedly different from that in wildtype animals, with many proliferating granule cells invading the cerebellar anlage. This appeared to be the first demonstration of the involvement of a G protein-coupled chemokine receptor in neuronal cell migration and patterning in the central nervous system. They suggested that the results are important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia.

Ma et al. (1998) found that mice deficient for Cxcr4 or its ligand Sdf1 died perinatally with defects in both the hemopoietic and nervous systems, whereas heterozygotes were normal. Reduced B-lymphopoiesis and myelopoiesis were observed in fetal liver, and myelopoiesis was absent in bone marrow; however, T-lymphopoiesis was normal. In the nervous system, the cerebellum developed with an irregular external granule cell layer, ectopically located Purkinje cells, and numerous chromophilic cell clumps of granule cells that had migrated abnormally within the cerebellar anlage.

CXCR4 mRNA is expressed at sites of neuronal and progenitor cell migration in the hippocampus at late embryonic and early postnatal ages. SDF1 mRNA, the only known ligand for the CXCR4 receptor, is expressed close to these migration sites, in the meninges investing the hippocampal primordium and in the primordium itself. In mice engineered to lack the CXCR4 receptor, Lu et al. (2002) found that the morphology of the hippocampal dentate gyrus was dramatically altered. Gene expression markers for dentate gyrus granule neurons and bromodeoxyuridine labeling of dividing cells showed an underlying defect in the stream of postmitotic cells and secondary dentate progenitor cells that migrate toward and form the dentate gyrus. In the absence of CXCR4, the number of dividing cells in the migratory stream and in the dentate gyrus itself was reduced, and neurons appeared to differentiate prematurely before reaching their target. Thus, Lu et al. (2002) concluded that the SDF1/CXCR4 chemokine signaling system has a role in dentate gyrus morphogenesis. The dentate gyrus is unusual as a site of adult neurogenesis. They found that both CXCR4 and SDF1 are expressed in the adult dentate gyrus, suggesting an ongoing role in dentate gyrus morphogenesis.

Knaut et al. (2003) applied genetics and in vivo imaging to show that 'odysseus,' a zebrafish homolog of the G protein-coupled chemokine receptor Cxcr4, is required specifically in germ cells for their chemotaxis. Odysseus mutant germ cells are able to activate the migratory program, but fail to undergo directed migration toward their target tissue, resulting in randomly dispersed germ cells. SDF1, the presumptive cognate ligand for Cxcr4, showed a similar loss of function phenotype and can recruit germ cells to ectopic sites in the embryo, thus identifying a vertebrate ligand-receptor pair guiding migratory germ cells at all stages of migration toward their target.

Ding et al. (2006) used the Cre-loxP system to delete the Vhl gene (608537) from podocytes in the glomerular basement membrane of mice. At about 4 weeks of age, the mice developed rapidly progressive renal disease with hematuria, proteinuria, and renal failure with crescentic glomerulonephritis with prominent segmental fibrin deposition and fibrinoid necrosis. No immune deposits were present; the phenotype was similar to human 'pauci-immune' rapidly progressive glomerulonephritis (RPGN). Gene expression profiling showed increased expression of the Cxcr4 gene in glomeruli from both mice and humans with RPGN. Treatment of the mice with a Cxcr4 antibody resulted in clinical improvement, and isolated overexpression of Cxcr4 was sufficient to cause glomerular disease. Ding et al. (2006) hypothesized that upregulation of Cxcr4 allowed terminally differentiated podocytes to reenter the cell cycle, proliferate, and form cellular crescents.

Kawai et al. (2007) transplanted human peripheral blood CD34 (142230)-positive stem cells expressing wildtype or WHIM-type mutated CXCR4 into nonobese diabetic/SCID mice. Neither wildtype nor mutated CXCR4 enhanced neutrophil apoptosis in stem cell cultures, even with CXCL12 stimulation. However, mutated CXCR4 further enhanced bone marrow engraftment and was associated with significantly increased apoptosis in bone marrow and reduced release of transduced white cells into peripheral blood. Kawai et al. (2007) concluded that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence rather than a direct effect of activation of mutated CXCR4.

Hirbe et al. (2007) created hematopoietic Cxcr4-null mice via fetal liver transplant. Compared with controls, mice reconstituted with Cxcr4-null hematopoietic cells exhibited elevated markers of bone resorption, increased osteoclast perimeter along bone, and increased bone loss. Cxcr4-null osteoclasts showed accelerated differentiation and enhanced bone resorption in vitro. Bone tumor growth was significantly increased in the mutant mice, and this enhanced bone tumor growth was abrogated with the osteoclast inhibitor zoledronic acid.

Nair and Schilling (2008) showed that the chemokine Cxcl12b (see 600835) and its receptor Cxcr4a restrict anterior migration of the endoderm during zebrafish gastrulation, thereby coordinating its movements with those of the mesoderm. Depletion of either gene product causes disruption of integrin-dependent cell adhesion, resulting in separation of the endoderm from the mesoderm; the endoderm then migrates farther anteriorly than it normally would, resulting in bilateral duplication of endodermal organs. Nair and Schilling (2008) suggested that this process may have relevance to human gastrointestinal bifurcations and other organ defects.

Repair of demyelinated lesions requires migration, proliferation, and differentiation of oligodendrocyte precursor cells, which originate in subventricular zones distant from white matter areas of the central nervous system. Patel et al. (2010) used cuprizone exposure to induce demyelination in adult mice and found that Cxcl12 and Cxcr4 were required for remyelination after cessation of cuprizone exposure. Cxcl12 was upregulated within activated astrocytes and microglia during the demyelination phase, followed by Cxcl12-induced upregulation of Cxcr4 in oligodendrocyte precursors during recovery. Loss of Cxcr4 signaling via either pharmacologic blockade or RNA silencing led to decreased oligodendrocyte precursor maturation and failure of remyelination.

Using mice, Whitman et al. (2018) developed an ex vivo slice assay to examine the routing of cranial nerves, including the oculomotor nerve (CN3), during development. Loss of Cxcr4 or Cxcl12 caused misrouting of the oculomotor nerve and trigeminal nerve with aberrant innervation of extraocular muscles. The findings were consistent with a mechanism for oculomotor synkinesis (see, e.g., 619215).


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 WHIM SYNDROME 1

CXCR4, ARG334TER
  
RCV000015063...

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous c.1000C-T transition in the CXCR4 gene, resulting in an arg334-to-ter (R334X) substitution. The mutation occurred on a CpG dinucleotide on 4 distinct haplotypes within the 4 separate pedigrees, consistent with recurrence. The R334X mutation resulted in truncation of 19 residues from the serine- and threonine-rich cytoplasmic tail, a domain involved in the regulation of receptor function. Lymphoblastoid cell lines carrying the R334X truncation mutation showed significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF1 (CXCL12; 600835), consistent with dysregulated signaling by the mutant receptor.

In a 6-year-old boy with WHIMS1 (UPN 5780) who had presented at age 1 year with salmonellosis, Beaussant Cohen et al. (2012) detected heterozygosity for the R334X mutation (c.1000C-T, NM_003467.2). Warts were not present in the patient.

Heusinkveld et al. (2019) stated that R334X is the most common CXCR4 mutation, accounting for about 50% of WHIMS1 cases.


.0002 WHIM SYNDROME 1

CXCR4, 2-BP DEL, 1016CT
  
RCV000015065...

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous 2-bp deletion (c.1016_1017delCT) in the CXCR4 gene, resulting in a frameshift and truncation of 13 residues (Ser339fs342Ter) from the serine- and threonine-rich cytoplasmic tail.


.0003 WHIM SYNDROME 1

CXCR4, GLU343TER
  
RCV001801239

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous c.1027G-T transversion in the CXCR4 gene, resulting in a glu343-to-ter (E343X) substitution, removing 10 residues from the cytoplasmic tail of the protein.


.0004 WHIM SYNDROME 1

CXCR4, SER338TER
  
RCV000015067...

In 2 sibs (family 1) with WHIM syndrome-1 (WHIMS1; 193670), Balabanian et al. (2005) identified a heterozygous c.1013C-G transversion in the CXCR4 gene, resulting in a ser338-to-ter (S338X) substitution causing partial deletion of the C terminus. T lymphocytes isolated from the patients showed impaired CXCL12-induced internalization of CXCR4 and enhanced activation of receptor-associated G proteins. Further studies showed that the mutant protein altered the function of the wildtype receptor by a transdominant-negative effect.

Beaussant Cohen et al. (2012) restudied (family 4) the family with the S338X mutation (c.1013C-G, NM_003467.2) described by Balabanian et al. (2005) and included 4 affected family members.

Variant Function

By functional expression studies in HEK cells, Lagane et al. (2008) found that S388X-mutant CXCR4 maintained association with beta-arrestin-2 (ARRB2; 107941), preserved downstream signaling, and even showed enhanced chemotactic responsiveness to the CXCR4 ligand CXCL12 compared to wildtype CXCR4. An SHSK motif in CXCR4 was necessary for ARRB2-dependent signaling. Mutant CXCR4 proteins were found to form functional heterodimers with wildtype CXCR4, which is consistent with a dominant-negative effect.


.0005 WHIM SYNDROME 1

CXCR4, 1-BP INS, 969G
  
RCV001339385...

In 3 members of a 2-generation family (family 1) with WHIM syndrome-1 (WHIMS1; 193670), Beaussant Cohen et al. (2012) identified a heterozygous 1-bp insertion (c.969_970insG, NM_003467.2) in the CXCR4 gene, resulting in a frameshift and premature termination (Gly323fs343Ter). The mutation was predicted to result in truncation of the C-terminal tail of the receptor that would impair the desensitization process.


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Cassandra L. Kniffin - updated : 07/02/2021
Cassandra L. Kniffin - updated : 03/01/2021
Ada Hamosh - updated : 06/30/2015
Ada Hamosh - updated : 2/3/2014
Patricia A. Hartz - updated : 11/13/2012
Ada Hamosh - updated : 2/2/2011
Paul J. Converse - updated : 4/21/2009
Cassandra L. Kniffin - updated : 3/10/2009
Ada Hamosh - updated : 11/5/2008
Cassandra L. Kniffin - updated : 6/3/2008
Paul J. Converse - updated : 3/19/2008
Patricia A. Hartz - updated : 2/29/2008
Patricia A. Hartz - updated : 9/3/2007
Paul J. Converse - updated : 6/18/2007
Paul J. Converse - updated : 4/10/2007
Cassandra L. Kniffin - updated : 11/1/2006
Paul J. Converse - updated : 9/20/2006
Paul J. Converse - updated : 5/15/2006
Paul J. Converse - updated : 10/27/2005
Patricia A. Hartz - updated : 5/12/2004
Ada Hamosh - updated : 9/23/2003
John A. Phillips, III - updated : 8/26/2003
Victor A. McKusick - updated : 5/30/2003
Denise L. M. Goh - updated : 4/18/2003
Victor A. McKusick - updated : 4/14/2003
Jane Kelly - updated : 3/14/2003
Ada Hamosh - updated : 2/5/2003
Paul J. Converse - updated : 7/22/2002
Victor A. McKusick - updated : 6/14/2002
Paul J. Converse - updated : 6/28/2001
Paul J. Converse - updated : 2/28/2001
Victor A. McKusick - updated : 11/27/2000
Paul J. Converse - updated : 7/17/2000
Paul J. Converse - updated : 6/6/2000
Ada Hamosh - updated : 2/9/1999
Victor A. McKusick - updated : 6/19/1998
Victor A. McKusick - updated : 6/19/1997
Victor A. McKusick - edited : 3/5/1997
Mark H. Paalman - updated : 8/28/1996
Mark H. Paalman - updated : 5/13/1996
Creation Date:
Victor A. McKusick : 9/16/1993
carol : 10/26/2021
alopez : 07/07/2021
ckniffin : 07/02/2021
alopez : 03/04/2021
ckniffin : 03/01/2021
alopez : 06/30/2015
carol : 2/9/2015
carol : 2/9/2015
alopez : 2/3/2014
terry : 4/4/2013
mgross : 11/13/2012
terry : 11/13/2012
terry : 9/14/2012
terry : 8/6/2012
alopez : 2/9/2011
terry : 2/2/2011
mgross : 4/22/2009
terry : 4/21/2009
wwang : 3/19/2009
ckniffin : 3/10/2009
alopez : 12/3/2008
alopez : 11/13/2008
terry : 11/5/2008
wwang : 6/17/2008
ckniffin : 6/3/2008
mgross : 3/20/2008
mgross : 3/20/2008
terry : 3/19/2008
mgross : 2/29/2008
carol : 9/7/2007
terry : 9/3/2007
mgross : 6/18/2007
mgross : 4/10/2007
wwang : 11/13/2006
ckniffin : 11/1/2006
mgross : 9/20/2006
carol : 6/21/2006
mgross : 6/1/2006
terry : 5/15/2006
mgross : 11/7/2005
terry : 10/27/2005
mgross : 5/13/2004
terry : 5/12/2004
ckniffin : 3/23/2004
ckniffin : 12/10/2003
alopez : 9/23/2003
alopez : 8/26/2003
tkritzer : 6/9/2003
tkritzer : 6/5/2003
terry : 5/30/2003
alopez : 4/30/2003
carol : 4/21/2003
terry : 4/18/2003
alopez : 4/16/2003
alopez : 4/16/2003
alopez : 4/16/2003
terry : 4/14/2003
cwells : 3/14/2003
alopez : 2/6/2003
terry : 2/5/2003
mgross : 9/26/2002
mgross : 7/22/2002
cwells : 7/1/2002
terry : 6/14/2002
mgross : 6/28/2001
mgross : 6/19/2001
alopez : 2/28/2001
alopez : 2/28/2001
alopez : 2/28/2001
mcapotos : 12/11/2000
mcapotos : 12/5/2000
terry : 11/27/2000
mgross : 7/17/2000
carol : 6/7/2000
carol : 6/6/2000
jlewis : 8/13/1999
alopez : 2/9/1999
alopez : 2/9/1999
alopez : 2/9/1999
dholmes : 7/22/1998
carol : 6/22/1998
terry : 6/19/1998
terry : 8/21/1997
mark : 6/19/1997
mark : 3/5/1997
carol : 9/16/1993

* 162643

CHEMOKINE, CXC MOTIF, RECEPTOR 4; CXCR4


Alternative titles; symbols

NEUROPEPTIDE Y RECEPTOR Y3; NPY3R
FUSIN
D2S201E
LEUKOCYTE-DERIVED SEVEN-TRANSMEMBRANE-DOMAIN RECEPTOR; LESTR
SEVEN-TRANSMEMBRANE-SEGMENT RECEPTOR, SPLEEN
HM89
LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 3; LAP3
LPS-ASSOCIATED PROTEIN 3


HGNC Approved Gene Symbol: CXCR4

Cytogenetic location: 2q22.1     Genomic coordinates (GRCh38): 2:136,114,349-136,118,149 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
2q22.1 Myelokathexis, isolated 193670 Autosomal dominant 3
WHIM syndrome 1 193670 Autosomal dominant 3

TEXT

Cloning and Expression

Several receptors for neuropeptide Y (NPY; 162640) have been demonstrated and shown to differ in pharmacologic characteristics, tissue distribution, and structure of the encoding genes; see the NPY Y1 receptor (NPY1R; 162641) and the NPY Y2 receptor (NPY2R; 162642). Herzog et al. (1993) cloned, sequenced, and mapped the human homolog of a proposed bovine NPY Y3 receptor reported by Rimland et al. (1991). The human cDNA clone was derived from a human lung cDNA library. The 1,670-bp sequence predicts a single open reading frame (ORF) of 352 amino acids, with 92% amino acid identity to the reported bovine sequence. The amino acid sequence shares features common to many other G protein-coupled receptors, including the 7-transmembrane regions and putative glycosylation and phosphorylation sites. The receptor shows 36% identity to the interleukin-8 receptor (IL8RA; 146929), which is located on chromosome 2, and to the angiotensin II receptor (AGTR1; 106165), but only 21% identity to the NPY Y1 receptor.

The recruitment of leukocytes to inflamed tissues involves interleukin-8 (IL8; 146930) and several related chemotactic cytokines that attract and activate leukocytes. Loetscher et al. (1994) noted that these proteins are similar in size, have marked sequence similarities, and are characterized by 4 conserved cysteines that form 2 essential disulfide bonds. Two subfamilies are distinguished according to the arrangement of the first 2 cysteines, which are either adjacent (CC subfamily) or separated by one amino acid (CXC subfamily). The CXC cytokines activate primarily neutrophil leukocytes, while CC cytokines act on monocytes, basophils, and eosinophils. These chemotactic agonists act via 7-transmembrane domain, G protein-coupled receptors, e.g., the 2 interleukin-8 receptors, IL8RA and IL8RB (146928). Chemotactic cytokines of the CC subfamily do not bind to IL8 receptors. Loetscher et al. (1994) isolated from a human blood monocyte cDNA library a cDNA clone encoding a protein of 352 amino acids, corresponding to a receptor of the 7-transmembrane domain, G protein-coupled type. They referred to the gene and the deduced protein as LESTR for 'leukocyte-derived seven-transmembrane domain receptor.' It shows 92.6% identity with a bovine neuropeptide Y receptor. In the monocyte library, LESTR cDNA fragments were about 20 times as frequent as cDNA coding for IL8RA and IL8RB, and much higher levels of mRNA specific for LESTR than for IL8R were found in human blood neutrophils and lymphocytes. Although the ligand for LESTR could not be identified among a large number of chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to IL8RA and IL8RB suggested to Loetscher et al. (1994) that LESTR may function in the activation of inflammatory cells.

The human CD4 molecule (186940) acts as the primary receptor for the human immunodeficiency virus type 1 (HIV-1), but CD4 supports viral entry into cells only when it is expressed on specific human cell types (Clapham et al., 1991). Weiner et al. (1991) and Dragic and Alizon (1993) presented evidence that the restriction of HIV-1 infection to certain human cell types is the result of a specific cofactor, encoded in the human genome, which is required for cell virus membrane fusion. Feng et al. (1996) undertook the isolation and characterization of the putative human HIV-1 fusion cofactor using an approach that made no assumptions about the mode of action of the cofactor other than that the cofactor would allow a CD4-expressing nonhuman cell to undergo viral fusion. They transfected CD4-expressing NIH 3T3 cells with a HeLa cell cDNA library and then incubated the transfected cells with an NIH 3T3 cell line expressing the HIV-1 Env gene (which is required by HIV-1 for fusion); transfected CD4+ cells that fused with Env-expressing cells could be distinguished by utilizing a lacZ biochemical marker specific to such fusion products. Feng et al. (1996) isolated a 1.7-kb human cDNA clone that allowed the CD4-expressing NIH 3T3 cells to undergo fusion. The cDNA contained a 352-codon ORF whose predicted amino acid sequence has 7 predicted transmembrane segments and resembles that of the G protein-coupled receptor superfamily. The predicted molecular weight of the protein is 39,745 Da and its primary sequence includes 2 potential N-linked glycosylation sites. The cDNA had in fact been cloned previously by Federsppiel et al. (1993) from a human fetal spleen cDNA library and was designated D2S201E. The predicted protein has 37% amino acid identity with the interleukin-8 receptor and is 93% identical to that of a cDNA isolated from bovine locus ceruleus, which apparently encodes a neuropeptide Y receptor.


Gene Structure

Wegner et al. (1998) determined the genomic organization and promoter function of CXCR4. The gene contains 2 exons of 103 and 1,563 bp separated by an intron of 2,132 bp between codons 5 and 6 of the coding sequence. Sequence analysis predicted that the promoter region includes a TATA box, a nuclear respiratory factor-1 (NRF1; 600879) site, and 2 GC boxes. Deletion of the NRF1 site abolished CXCR4 promoter activity. Electrophoretic mobility shift assay (EMSA) experiments demonstrated that the transcriptional regulator NRF1 binds to the NRF1 site in the CXCR4 promoter. Caruz et al. (1998) also reported the genomic structure of CXCR4.


Mapping

By PCR analysis of human/hamster hybrid cell DNA, Herzog et al. (1993) showed that the NPY3R gene is located on human chromosome 2.

Federsppiel et al. (1993) localized D2S201E, the expressed segment encoding fusin, to chromosome 2q21 by isotopic in situ hybridization. This finding was corroborated by the mapping of the NPY3R gene to chromosome 2 by Herzog et al. (1993).


Biochemical Features

Crystal Structure

Wu et al. (2010) reported 5 independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5- to 3.2-angstrom resolution. All structures revealed a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. Wu et al. (2010) concluded that these structures provided new clues about the interactions between CXCR4 and its natural ligand CXCL12 (600835) and with the HIV-1 glycoprotein gp120.

Qin et al. (2015) reported the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1-angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic 2-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.


Gene Function

Herzog et al. (1993) reported that NPY and a number of other ligands failed to induce any change in cytosolic calcium levels in transfected cells, suggesting that this clone represented a novel neuropeptide receptor. Jazin et al. (1993) independently found that the Y3 receptor does not respond to NPY.

Feng et al. (1996) showed that transient expression of the CXCR4 gene (called 'fusin' by the authors) allowed nonhuman cells coexpressing recombinant CD4 to undergo Env-CD4-mediated cell fusion and productive HIV-1 infection. The authors used Northern analysis to show that fusin mRNA levels correlated with HIV-1 permissiveness in diverse human cell types; Federsppiel et al. (1993) had previously found that D2S201E was expressed in a variety of tissues, including brain and tissues of hemopoietic origin. Feng et al. (1996) also showed that anti-fusin antibodies strongly inhibited HIV-1 infection of normal human CD4+ target cells. The authors commented that the identification of fusin as a fusion cofactor for T-cell line-tropic HIV-1 isolates provided a new means of elucidating the mechanism of HIV-1 infection and suggested that production of an effective small-animal model of HIV infection might be possible.

Bleul et al. (1996) and Oberlin et al. (1996) reported that stromal cell-derived factor-1 (SDF1; 600835), also known as CXCL12 and PBSF, is a ligand for this receptor, which they referred to as CXCR4. Both groups found that SDF1 is a potent inhibitor in vitro of infection by lymphocyte-tropic HIV-1 strains. Oberlin et al. (1996) showed that the CC chemokines MIP-1-alpha (182283), MIP-1-beta (182284), and RANTES (187011), which inhibit monocyte-tropic HIV-1 infection via the CC chemokine receptor CMKBR5 (CCR5; 601373), were inactive against lymphocyte-tropic HIV-1 strains. Conversely, Bleul et al. (1996) showed that SDF1 does not inhibit CMKBR5-mediated infection by macrophage-tropic and dual-tropic HIV-1.

CCR5 is the major macrophage-tropic coreceptor for HIV-1, whereas CXCR4 serves the counterpart function for T cell-tropic viruses. Xiao et al. (2000) provided an explanation for the mystery of why only R5-HIV-1 is initially detected in new seroconvertors who are exposed to R5 and X4 viruses. Indeed, X4 virus emerges in a minority of patients and only in the late stages of disease, suggesting that early negative selection against HIV-1-CXCR4 interaction may exist. Xiao et al. (2000) reported that the HIV-1 Tat protein (HTATIP; 601409), which is secreted from virus-infected cells, is a CXCR4-specific antagonist. Soluble Tat selectively inhibited the entry and replication of X4, but not R5, virus in peripheral blood mononuclear cells. The authors proposed that one functional consequence of secreted Tat is to select against X4 viruses, thereby influencing the early in vivo course of HIV-1 disease.

Peled et al. (1999) demonstrated that SDF1 and its receptor CXCR4 are critical for murine bone marrow engraftment by human SCID repopulating stem cells. Treatment of human cells with anti-CXCR antibodies prevented engraftment. They further demonstrated that CD34(+)CD38(-/low) cells could be converted to CD34(+)CD38(-/low)CXCR4(+) stem cells by pretreatment with IL6 (147620) and stem cell factor (KITLG; 184745), which increased CXCR4 expression. This pretreatment potentiated migration to SDF1 and engraftment in primary and secondary transplanted mice.

Breast cancer metastasis occurs in a distinct pattern involving the regional lymph nodes, bone marrow, lung, and liver, but rarely other organs. By real-time quantitative PCR, immunohistochemistry, and flow cytometric analysis, Muller et al. (2001) found that CXCR4 is highly expressed in primary and metastatic human breast cancer cells but is undetectable in normal mammary tissue, whereas CCR7 (600242) is significantly expressed in normal tissue and is upregulated in breast cancer cells. Quantitative PCR analysis also detected peak expression levels of the CXCR4 ligand, CXCL12 (SDF1) in lymph nodes, lung, liver, and bone marrow, while the CCR7 ligand, CCL21 (602737), is most abundant in lymph nodes, the organs to which primary breast cancer cells preferentially migrate. Analysis of malignant melanomas determined that in addition to CXCR4 and CCR7, these tumors also had high levels of CCR10 (600240); its primary ligand is CCL27 (604833), a skin-specific chemokine involved in the homing of memory T cells into the skin. Flow cytometric analysis and confocal laser microscopy demonstrated that either CXCL12 or CCL21 induces high levels of F-actin polymerization and pseudopod formation in breast cancer cells. These chemokines, as well as lung and liver extracts, also induce directional migration of breast cancer cells in vitro, which can be blocked by antibodies to CXCR4 or CCL21. Histologic and quantitative PCR analyses showed that metastasis of intravenously or orthotopically injected breast cancer cells could be significantly decreased in SCID mice by treatment with anti-CXCR4 antibodies. Muller et al. (2001) proposed that the nonrandom expression of chemokine receptors in breast cancer and malignant melanoma, and probably in other tumor types, indicates that small molecule antagonists of chemokine receptors (e.g., Hendrix et al. (2000)) may be useful to interfere with tumor progression and metastasis in tumor patients.

Chan et al. (2003) investigated the expression of chemokines and chemokine receptors in eyes with primary intraocular B-cell lymphoma (PIOL). All 3 PIOL eyes showed similar pathology, with typical diffuse large B-lymphoma cells between the retinal pigment epithelium (RPE) and Bruch membrane. The eyes also showed a similar chemokine profile with the expression of CXCR4 and CXCR5 (BLR1; 601613) in the lymphoma cells. CXCL13 (605149) and CXCL12 transcripts were found only in the RPE and not in the malignant cells. No chemokine expression was detected on the RPE cells of a normal control eye. Since chemokines and chemokine receptors selective for B cells were identified in RPE and malignant B cells in eyes with PIOL, inhibition of B-cell chemoattractants might be a future strategy for the treatment of PIOL.

Liotta (2001) reviewed the theories explaining the bias of metastases toward certain organs and addressed questions raised by the work of Muller et al. (2001).

CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, Triantafilou et al. (2001) identified 4 diverse proteins, heat-shock cognate protein (HSPA8; 600816), HSP90A (HSPCA; 140571), chemokine receptor CXCR4, and growth/differentiation factor-5 (GDF5; 601146), on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. Triantafilou et al. (2001) proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens.

Levesque et al. (2003) demonstrated that the mobilization of hematopoietic progenitor cells (HPCs) by granulocyte colony-stimulating factor (GCSF; 138970) or cyclophosphamide was due to the disruption of the CXCR4/CXCL12 chemotactic pathway. The mobilization of HPCs coincided in vivo with the cleavage of the N terminus of the chemokine receptor CXCR4 found on HPCs. This resulted in the loss of chemotactic response of the HPCs to the CXCR4 ligand, CXCL12. The concentration of CXCL12 was also decreased in vivo in the bone marrow of mobilized mice, and this decrease coincided with the accumulation of serine proteases capable of direct cleavage and inactivation of CXCL12. As both CXCL12 and CXCR4 are essential for the homing and retention of HPCs in the bone marrow, the proteolytic degradation of CXCL12 and CXCR4 may represent a critical step in the mobilization of HPCs into the peripheral blood by GCSF or cyclophosphamide.

Ichiyama et al. (2003) showed that a low molecular mass nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic HIV-1 in cultured cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXCR4 receptor but not via CCR5. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography-mass spectrometry. Thus, KRH-1636 seemed to be a promising agent for the treatment of HIV-1 infection.

Hwang et al. (2003) characterized the expression of CXCR4 and analyzed its functions in ARO cells, a human anaplastic thyroid carcinoma (ATC) cell line. Fluorescence-activated cell sorting (FACS) analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA (both human thyroid carcinoma cell lines), and normal thyroid cells did not express membrane CXCR4, as determined by FACS. The authors concluded that these findings suggested that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.

Staller et al. (2003) demonstrated that the von Hippel-Lindau tumor suppressor protein (VHL; see 608537) negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF1-alpha; 603348) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. Staller et al. (2003) concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

Marchese et al. (2003) determined that AIP4 colocalized with CXCR4 at the plasma membrane in transfected HEK293 cells and that it colocalized with HRS (604375) on endosomes in transfected HeLa cells. AIP4, HRS, and a vacuole sorting protein, VPS4, were required for targeting CXCR4 to the degradative pathway.

The germinal center (GC) is organized into dark and light zones. B cells in the dark zone, called centroblasts, undergo rapid proliferation and somatic hypermutation of their antibody variable genes. Centroblasts then become smaller, nondividing centrocytes and undergo selection in the light zone based on the affinity of their surface antibody for the inducing antigen. The light zone also contains helper T cells and follicular dendritic cells that sequester antigen. Failure to differentiate results in centrocyte apoptosis, whereas centrocytes that bind antigen and receive T-cell help emigrate from the GC as long-lived plasma cells or memory B cells. Some centrocytes may also return to the dark zone for further proliferation and mutation. Using genetic and pharmacologic approaches, Allen et al. (2004) showed that CXCR4 was essential for GC dark and light zone segregation. In the presence of the antiapoptotic BCL2 (151430), B cells had robust chemotactic responses to the CXCR4 ligand, CXCL12, as well as to CXCL13, the ligand for CXCR5. CXCL12 was more abundant in the dark zone, and CXCR4 was more abundant on centroblasts than centrocytes. In contrast, CXCR5 helped direct cells to the CXCL13-positive light zone, but was not essential for segregation of the 2 zones. CXCL13 and CXCR5 were required for correct positioning of the light zone. Allen et al. (2004) concluded that these chemokines and their receptors are critical for movement of cells to different parts of the GC and for creating the distinct histologic appearance of the GC. They suggested that GC organization is likely to be disrupted in individuals with WHIM syndrome (WHIMS; 193670) resulting from C-terminal truncation mutations in CXCR4.

Using immunofluorescence microscopy, Yeaman et al. (2004) examined expression of the HIV receptors CD4 and galactosylceramide (see GALC; 606890) and the HIV coreceptors CXCR4 and CCR5 in ectocervical specimens from hysterectomy patients with benign diseases. CD4 expression was detected on epithelial cells at early and midproliferative stages of the menstrual cycle, whereas galactosylceramide expression was uniform in all stages of the menstrual cycle. CXCR4 was not detected on ectocervical epithelial cells, whereas CCR5 was expressed on ectocervical epithelial cells at all stages of the menstrual cycle. CD4-positive leukocytes were present in the basal and precornified layers of squamous epithelium during early and midproliferative phases of the menstrual cycle, but were absent in later proliferative phases and the secretory phase; the presence of CD4-positive leukocytes was not related to inflammation. Yeaman et al. (2004) concluded that HIV infection of the ectocervix most likely occurs through galactosylceramide and CCR5.

Feng et al. (2006) found that beta-defensin-3 (HBD3, or DEFB103A; 606611) not only blocked HIV-1 replication via direct interaction with virions and modulation of the CXCR4 coreceptor, but it also competed with the CXCR4 ligand, SDF1, and promoted internalization of CXCR4 without inducing calcium flux, ERK (see MAPK3; 601795) phosphorylation, or chemotaxis. HBD3 had no effect on other G protein-coupled receptors (e.g., CCR5). Feng et al. (2006) proposed that HBD3 or its derivatives may have potential for HIV and/or immunoregulatory therapy.

Jin et al. (2006) found that hematopoietic cytokines, particularly Kitlg and Tpo (THPO; 600044), induced release of Sdf1 from mouse platelets and enhanced neovascularization of ischemic hindlimbs through mobilization of Cxcr4-positive/Vegfr (KDR; 191306)-positive hematopoietic progenitors termed hemangiocytes. Revascularization was profoundly impaired in Mmp9 (120361)-deficient mice, which have impaired release of soluble Kitlg from membrane Kitlg, as well as Tpo-deficient mice and Tpor (MPL; 159530)-deficient mice. Transplantation of Cxcr4-positive/Vegfr-positive hemangiocytes restored revascularization in Mmp9-deficient mice. Jin et al. (2006) concluded that hematopoietic cytokines, through graded deployment of platelet-derived SDF1, support mobilization and recruitment of CXCR4-positive/VEGFR-positive hemangiocytes.

Vasyutina et al. (2005) showed that migrating muscle progenitors express Cxcr4 and noted that the Cxcr4 ligand Sdf1 is expressed in limb and branchial arch mesenchyme, i.e., along the routes and at the targets of migratory cells. Ectopic application of Sdf1 in chick limb attracted muscle progenitor cells. In Cxcr4 mutant mice, the number of muscle progenitors that colonized the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of muscle progenitor cells was accompanied by increased apoptosis, indicating that Cxcr4 signals provide not only attractive cues, but also control survival. Vasyutina et al. (2005) further found that muscle progenitors of Cxcr4/Gab1 (604439) double mutants did not reach the anlage of the tongue, suggesting that these proteins interact during progenitor cell migration.

Using immunohistochemistry, Lieberam et al. (2005) showed that mouse ventral motor neurons (vMNs) transiently expressed Cxcr4 as they followed their ventral trajectory, whereas Cxcl12 was expressed by mesenchymal cells surrounding the ventral neural tube. In mice lacking Cxcr4 or Cxcl12, vMNs adopted a dorsal motor neuron (dMN)-like trajectory. Axons of Cxcr4-deficient vMNs frequently invaded sensory ganglia, a characteristic dMN trajectory. Lieberam et al. (2005) concluded that a G protein-coupled receptor signaling system controls the precision of initial motor axon trajectories and that CXCR4 is a crucial effector of the transcriptional pathway specifying vMN connectivity.

By studying brains of mice and humans with West Nile virus (WNV; see 610379) encephalitis, McCandless et al. (2008) found downregulation of the beta isoform of CXCL12, but not the alpha isoform, as well as a decline of perivascular T cells and an increase in parenchymal T cells. Treatment with a continuously administered Cxcr4 antagonist increased the survival of WNV-infected mice and eventually caused a reduction in WNV burden in the brain. Cxcr4 antagonism also enhanced T-cell penetration in the brain after WNV encephalitis, increased virus-specific Cd8-positive T-cell interaction with infected cells, and decreased glial cell activation in infected brains. McCandless et al. (2008) proposed that targeting CXCR4 may allow enhanced CD8-positive T-cell infiltration without increased immunopathology in viral infections of the central nervous system.

Ding et al. (2014) combined an inducible endothelial cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury to show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The profibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor ID1 (600349), deploying proregenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive Fgfr1 (136350) signaling in liver sinusoidal endothelial cells counterbalanced Cxcr7-dependent proregenerative response and augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin (125660)-positive hepatic stellate-like cells and enforcing a profibrotic vascular niche. Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice restored the proregenerative pathway and prevented Fgfr1-mediated maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Ding et al. (2014) demonstrated that in response to liver injury, differential recruitment of proregenerative CXCR7-ID1 versus profibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis.


Molecular Genetics

WHIM syndrome-1 (WHIMS1; 193670) is an autosomal dominant immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis (kathexis = retention). The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be particularly important in the natural control of this infection. By genomewide scan, Hernandez et al. (2003) mapped the gene mutant in WHIMS1 to a region of roughly 12 cM on 2q21, and by screening the most attractive positional candidate in this region, CXCR4, they identified truncating mutations in the cytoplasmic tail domain of the CXCR4 gene (162643.0001-162643.0003) in 6 unrelated families with WHIMS1.

Balabanian et al. (2005) identified a heterozygous nonsense mutation in the CXCR4 gene (S338X; 162643.0004) in 2 sibs with WHIMS1.

In 8 patients from 3 unrelated families with WHIMS1, Beaussant Cohen et al. (2012) identified heterozygous nonsense or frameshift mutations in the CXCR4 gene (see, e.g., 162643.0001, 162643.0004, 162643.0005). The distal truncations of the C-tail of the protein were predicted to remove potential phosphorylation sites involved in the attenuation process. The findings were consistent with a gain-of-function effect. Family 4 had previously been reported by Balabanian et al. (2005).


Nomenclature

Depending on what properties were being studied, this molecule has been called neuropeptide Y receptor Y3, fusin, and leukocyte-derived 7-transmembrane-domain receptor, among various designations.


Animal Model

Vascularization of organs generally occurs by remodeling of the preexisting vascular system during their differentiation and growth to enable them to perform their specific functions during development. The molecules required for early vascular systems, many of which are receptor tyrosine kinases and their ligands, are revealed by analysis of mutant mice. As most of these mice die during early gestation before many of their organs have developed, the molecules responsible for vascularization during organogenesis are not identified by this approach. CXCR4 is responsible for B-cell lymphopoiesis, bone marrow myelopoiesis, and cardiac ventricular septum formation. CXCR4 also functions as a coreceptor for HIV-1 and is a receptor for the CXC chemokine PBSF/SDF1 (600835). Tachibana et al. (1998) showed that CXCR4 is expressed in developing vascular endothelial cells. Tachibana et al. (1998) found that mice lacking either CXCR4 or PBSF/SDF1 have defective formation of the large vessels supplying the gastrointestinal tract. In addition, mice lacking CXCR4 die in utero and are defective in vascular development, hematopoiesis and cardiogenesis, like mice lacking PBSF/SDF1, indicating that CXCR4 is a primary physiologic receptor for PBSF/SDF1. Tachibana et al. (1998) concluded that PBSF/SDF1 and CXCR4 define a new signaling system for organ vascularization.

Zou et al. (1998) pointed out that CXCR4 is broadly expressed in cells of both the immune and the central nervous systems and can mediate migration of resting leukocytes and hematopoietic progenitors in response to its ligand, SDF1. They showed that mice lacking CXCR4 exhibit hematopoietic and cardiac defects identical to those of SDF1-deficient mice (Nagasawa et al., 1996), indicating that CXCR4 may be the only receptor for SDF1. Furthermore, fetal cerebellar development in mutant animals was markedly different from that in wildtype animals, with many proliferating granule cells invading the cerebellar anlage. This appeared to be the first demonstration of the involvement of a G protein-coupled chemokine receptor in neuronal cell migration and patterning in the central nervous system. They suggested that the results are important for designing strategies to block HIV entry into cells and for understanding mechanisms of pathogenesis in AIDS dementia.

Ma et al. (1998) found that mice deficient for Cxcr4 or its ligand Sdf1 died perinatally with defects in both the hemopoietic and nervous systems, whereas heterozygotes were normal. Reduced B-lymphopoiesis and myelopoiesis were observed in fetal liver, and myelopoiesis was absent in bone marrow; however, T-lymphopoiesis was normal. In the nervous system, the cerebellum developed with an irregular external granule cell layer, ectopically located Purkinje cells, and numerous chromophilic cell clumps of granule cells that had migrated abnormally within the cerebellar anlage.

CXCR4 mRNA is expressed at sites of neuronal and progenitor cell migration in the hippocampus at late embryonic and early postnatal ages. SDF1 mRNA, the only known ligand for the CXCR4 receptor, is expressed close to these migration sites, in the meninges investing the hippocampal primordium and in the primordium itself. In mice engineered to lack the CXCR4 receptor, Lu et al. (2002) found that the morphology of the hippocampal dentate gyrus was dramatically altered. Gene expression markers for dentate gyrus granule neurons and bromodeoxyuridine labeling of dividing cells showed an underlying defect in the stream of postmitotic cells and secondary dentate progenitor cells that migrate toward and form the dentate gyrus. In the absence of CXCR4, the number of dividing cells in the migratory stream and in the dentate gyrus itself was reduced, and neurons appeared to differentiate prematurely before reaching their target. Thus, Lu et al. (2002) concluded that the SDF1/CXCR4 chemokine signaling system has a role in dentate gyrus morphogenesis. The dentate gyrus is unusual as a site of adult neurogenesis. They found that both CXCR4 and SDF1 are expressed in the adult dentate gyrus, suggesting an ongoing role in dentate gyrus morphogenesis.

Knaut et al. (2003) applied genetics and in vivo imaging to show that 'odysseus,' a zebrafish homolog of the G protein-coupled chemokine receptor Cxcr4, is required specifically in germ cells for their chemotaxis. Odysseus mutant germ cells are able to activate the migratory program, but fail to undergo directed migration toward their target tissue, resulting in randomly dispersed germ cells. SDF1, the presumptive cognate ligand for Cxcr4, showed a similar loss of function phenotype and can recruit germ cells to ectopic sites in the embryo, thus identifying a vertebrate ligand-receptor pair guiding migratory germ cells at all stages of migration toward their target.

Ding et al. (2006) used the Cre-loxP system to delete the Vhl gene (608537) from podocytes in the glomerular basement membrane of mice. At about 4 weeks of age, the mice developed rapidly progressive renal disease with hematuria, proteinuria, and renal failure with crescentic glomerulonephritis with prominent segmental fibrin deposition and fibrinoid necrosis. No immune deposits were present; the phenotype was similar to human 'pauci-immune' rapidly progressive glomerulonephritis (RPGN). Gene expression profiling showed increased expression of the Cxcr4 gene in glomeruli from both mice and humans with RPGN. Treatment of the mice with a Cxcr4 antibody resulted in clinical improvement, and isolated overexpression of Cxcr4 was sufficient to cause glomerular disease. Ding et al. (2006) hypothesized that upregulation of Cxcr4 allowed terminally differentiated podocytes to reenter the cell cycle, proliferate, and form cellular crescents.

Kawai et al. (2007) transplanted human peripheral blood CD34 (142230)-positive stem cells expressing wildtype or WHIM-type mutated CXCR4 into nonobese diabetic/SCID mice. Neither wildtype nor mutated CXCR4 enhanced neutrophil apoptosis in stem cell cultures, even with CXCL12 stimulation. However, mutated CXCR4 further enhanced bone marrow engraftment and was associated with significantly increased apoptosis in bone marrow and reduced release of transduced white cells into peripheral blood. Kawai et al. (2007) concluded that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence rather than a direct effect of activation of mutated CXCR4.

Hirbe et al. (2007) created hematopoietic Cxcr4-null mice via fetal liver transplant. Compared with controls, mice reconstituted with Cxcr4-null hematopoietic cells exhibited elevated markers of bone resorption, increased osteoclast perimeter along bone, and increased bone loss. Cxcr4-null osteoclasts showed accelerated differentiation and enhanced bone resorption in vitro. Bone tumor growth was significantly increased in the mutant mice, and this enhanced bone tumor growth was abrogated with the osteoclast inhibitor zoledronic acid.

Nair and Schilling (2008) showed that the chemokine Cxcl12b (see 600835) and its receptor Cxcr4a restrict anterior migration of the endoderm during zebrafish gastrulation, thereby coordinating its movements with those of the mesoderm. Depletion of either gene product causes disruption of integrin-dependent cell adhesion, resulting in separation of the endoderm from the mesoderm; the endoderm then migrates farther anteriorly than it normally would, resulting in bilateral duplication of endodermal organs. Nair and Schilling (2008) suggested that this process may have relevance to human gastrointestinal bifurcations and other organ defects.

Repair of demyelinated lesions requires migration, proliferation, and differentiation of oligodendrocyte precursor cells, which originate in subventricular zones distant from white matter areas of the central nervous system. Patel et al. (2010) used cuprizone exposure to induce demyelination in adult mice and found that Cxcl12 and Cxcr4 were required for remyelination after cessation of cuprizone exposure. Cxcl12 was upregulated within activated astrocytes and microglia during the demyelination phase, followed by Cxcl12-induced upregulation of Cxcr4 in oligodendrocyte precursors during recovery. Loss of Cxcr4 signaling via either pharmacologic blockade or RNA silencing led to decreased oligodendrocyte precursor maturation and failure of remyelination.

Using mice, Whitman et al. (2018) developed an ex vivo slice assay to examine the routing of cranial nerves, including the oculomotor nerve (CN3), during development. Loss of Cxcr4 or Cxcl12 caused misrouting of the oculomotor nerve and trigeminal nerve with aberrant innervation of extraocular muscles. The findings were consistent with a mechanism for oculomotor synkinesis (see, e.g., 619215).


ALLELIC VARIANTS 5 Selected Examples):

.0001   WHIM SYNDROME 1

CXCR4, ARG334TER
SNP: rs104893624, ClinVar: RCV000015063, RCV001509163, RCV001801237

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous c.1000C-T transition in the CXCR4 gene, resulting in an arg334-to-ter (R334X) substitution. The mutation occurred on a CpG dinucleotide on 4 distinct haplotypes within the 4 separate pedigrees, consistent with recurrence. The R334X mutation resulted in truncation of 19 residues from the serine- and threonine-rich cytoplasmic tail, a domain involved in the regulation of receptor function. Lymphoblastoid cell lines carrying the R334X truncation mutation showed significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF1 (CXCL12; 600835), consistent with dysregulated signaling by the mutant receptor.

In a 6-year-old boy with WHIMS1 (UPN 5780) who had presented at age 1 year with salmonellosis, Beaussant Cohen et al. (2012) detected heterozygosity for the R334X mutation (c.1000C-T, NM_003467.2). Warts were not present in the patient.

Heusinkveld et al. (2019) stated that R334X is the most common CXCR4 mutation, accounting for about 50% of WHIMS1 cases.


.0002   WHIM SYNDROME 1

CXCR4, 2-BP DEL, 1016CT
SNP: rs730880320, ClinVar: RCV000015065, RCV001801238

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous 2-bp deletion (c.1016_1017delCT) in the CXCR4 gene, resulting in a frameshift and truncation of 13 residues (Ser339fs342Ter) from the serine- and threonine-rich cytoplasmic tail.


.0003   WHIM SYNDROME 1

CXCR4, GLU343TER
SNP: rs104893625, ClinVar: RCV001801239

Hernandez et al. (2003) found that affected members of a family with WHIM syndrome-1 (WHIMS1; 193670) had a heterozygous c.1027G-T transversion in the CXCR4 gene, resulting in a glu343-to-ter (E343X) substitution, removing 10 residues from the cytoplasmic tail of the protein.


.0004   WHIM SYNDROME 1

CXCR4, SER338TER
SNP: rs104893626, ClinVar: RCV000015067, RCV001568992, RCV001801240

In 2 sibs (family 1) with WHIM syndrome-1 (WHIMS1; 193670), Balabanian et al. (2005) identified a heterozygous c.1013C-G transversion in the CXCR4 gene, resulting in a ser338-to-ter (S338X) substitution causing partial deletion of the C terminus. T lymphocytes isolated from the patients showed impaired CXCL12-induced internalization of CXCR4 and enhanced activation of receptor-associated G proteins. Further studies showed that the mutant protein altered the function of the wildtype receptor by a transdominant-negative effect.

Beaussant Cohen et al. (2012) restudied (family 4) the family with the S338X mutation (c.1013C-G, NM_003467.2) described by Balabanian et al. (2005) and included 4 affected family members.

Variant Function

By functional expression studies in HEK cells, Lagane et al. (2008) found that S388X-mutant CXCR4 maintained association with beta-arrestin-2 (ARRB2; 107941), preserved downstream signaling, and even showed enhanced chemotactic responsiveness to the CXCR4 ligand CXCL12 compared to wildtype CXCR4. An SHSK motif in CXCR4 was necessary for ARRB2-dependent signaling. Mutant CXCR4 proteins were found to form functional heterodimers with wildtype CXCR4, which is consistent with a dominant-negative effect.


.0005   WHIM SYNDROME 1

CXCR4, 1-BP INS, 969G
SNP: rs1684840786, ClinVar: RCV001339385, RCV001801249

In 3 members of a 2-generation family (family 1) with WHIM syndrome-1 (WHIMS1; 193670), Beaussant Cohen et al. (2012) identified a heterozygous 1-bp insertion (c.969_970insG, NM_003467.2) in the CXCR4 gene, resulting in a frameshift and premature termination (Gly323fs343Ter). The mutation was predicted to result in truncation of the C-terminal tail of the receptor that would impair the desensitization process.


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Contributors:
Cassandra L. Kniffin - updated : 07/02/2021
Cassandra L. Kniffin - updated : 03/01/2021
Ada Hamosh - updated : 06/30/2015
Ada Hamosh - updated : 2/3/2014
Patricia A. Hartz - updated : 11/13/2012
Ada Hamosh - updated : 2/2/2011
Paul J. Converse - updated : 4/21/2009
Cassandra L. Kniffin - updated : 3/10/2009
Ada Hamosh - updated : 11/5/2008
Cassandra L. Kniffin - updated : 6/3/2008
Paul J. Converse - updated : 3/19/2008
Patricia A. Hartz - updated : 2/29/2008
Patricia A. Hartz - updated : 9/3/2007
Paul J. Converse - updated : 6/18/2007
Paul J. Converse - updated : 4/10/2007
Cassandra L. Kniffin - updated : 11/1/2006
Paul J. Converse - updated : 9/20/2006
Paul J. Converse - updated : 5/15/2006
Paul J. Converse - updated : 10/27/2005
Patricia A. Hartz - updated : 5/12/2004
Ada Hamosh - updated : 9/23/2003
John A. Phillips, III - updated : 8/26/2003
Victor A. McKusick - updated : 5/30/2003
Denise L. M. Goh - updated : 4/18/2003
Victor A. McKusick - updated : 4/14/2003
Jane Kelly - updated : 3/14/2003
Ada Hamosh - updated : 2/5/2003
Paul J. Converse - updated : 7/22/2002
Victor A. McKusick - updated : 6/14/2002
Paul J. Converse - updated : 6/28/2001
Paul J. Converse - updated : 2/28/2001
Victor A. McKusick - updated : 11/27/2000
Paul J. Converse - updated : 7/17/2000
Paul J. Converse - updated : 6/6/2000
Ada Hamosh - updated : 2/9/1999
Victor A. McKusick - updated : 6/19/1998
Victor A. McKusick - updated : 6/19/1997
Victor A. McKusick - edited : 3/5/1997
Mark H. Paalman - updated : 8/28/1996
Mark H. Paalman - updated : 5/13/1996

Creation Date:
Victor A. McKusick : 9/16/1993

Edit History:
carol : 10/26/2021
alopez : 07/07/2021
ckniffin : 07/02/2021
alopez : 03/04/2021
ckniffin : 03/01/2021
alopez : 06/30/2015
carol : 2/9/2015
carol : 2/9/2015
alopez : 2/3/2014
terry : 4/4/2013
mgross : 11/13/2012
terry : 11/13/2012
terry : 9/14/2012
terry : 8/6/2012
alopez : 2/9/2011
terry : 2/2/2011
mgross : 4/22/2009
terry : 4/21/2009
wwang : 3/19/2009
ckniffin : 3/10/2009
alopez : 12/3/2008
alopez : 11/13/2008
terry : 11/5/2008
wwang : 6/17/2008
ckniffin : 6/3/2008
mgross : 3/20/2008
mgross : 3/20/2008
terry : 3/19/2008
mgross : 2/29/2008
carol : 9/7/2007
terry : 9/3/2007
mgross : 6/18/2007
mgross : 4/10/2007
wwang : 11/13/2006
ckniffin : 11/1/2006
mgross : 9/20/2006
carol : 6/21/2006
mgross : 6/1/2006
terry : 5/15/2006
mgross : 11/7/2005
terry : 10/27/2005
mgross : 5/13/2004
terry : 5/12/2004
ckniffin : 3/23/2004
ckniffin : 12/10/2003
alopez : 9/23/2003
alopez : 8/26/2003
tkritzer : 6/9/2003
tkritzer : 6/5/2003
terry : 5/30/2003
alopez : 4/30/2003
carol : 4/21/2003
terry : 4/18/2003
alopez : 4/16/2003
alopez : 4/16/2003
alopez : 4/16/2003
terry : 4/14/2003
cwells : 3/14/2003
alopez : 2/6/2003
terry : 2/5/2003
mgross : 9/26/2002
mgross : 7/22/2002
cwells : 7/1/2002
terry : 6/14/2002
mgross : 6/28/2001
mgross : 6/19/2001
alopez : 2/28/2001
alopez : 2/28/2001
alopez : 2/28/2001
mcapotos : 12/11/2000
mcapotos : 12/5/2000
terry : 11/27/2000
mgross : 7/17/2000
carol : 6/7/2000
carol : 6/6/2000
jlewis : 8/13/1999
alopez : 2/9/1999
alopez : 2/9/1999
alopez : 2/9/1999
dholmes : 7/22/1998
carol : 6/22/1998
terry : 6/19/1998
terry : 8/21/1997
mark : 6/19/1997
mark : 3/5/1997
carol : 9/16/1993