The CXCR4 gene at 2q22.1 codes for C-X-C chemokine receptor type 4 (fusin, stromal cell-derived factor 1 receptor) which acts as a co-receptor (with CD4 being primary receptor) for some HIV isolates on T-cells (the other co-receptor being CCR5).
This is the natural receptor for stromal cell-derived factor 1 (CXCL12/SDF-1) that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. When phosphorylated on agonist stimulation, this leads to recruitment of ITCH, ubiquitination and protein degradation. It has key roles in haematopoiesis, cardiac ventricular septum formation, vascularization of the gastrointestinal tract, and cerebellar development. It binds to bacterial lipopolysaccharide (LPS) so mediating the LPS-induced inflammatory response, including TNF secretion by monocytes. Other interactions include with CD164, HIV-1 surface protein gp120 and Tat, extracellular ubiquitin and human cytomegalovirus/HHV-5 protein UL78.
The CXCR4 gene contains 2 exons and an intron between codons 5 and 6 of the coding sequence.
- Warts - disseminated and refractory extensive human papillomavirus (HPV) infection
- Myelokathexis (retention of neutrophils in the bone marrow).
In turn it is associated with neutropenia and lymphopenia. In 2015 WHIM syndrome became the first ever genetic condition where the cause of a miraculous cure in an individual was characterised to be a stem cell spontaneous mutation that resulted in deletion of the mutated gene (chromothripsis - more commonly associated with malignacy) . The CXCR4 antagonist plerixafor is in development as possible treatment.
- ↑ Dotta L, Tassone L, Badolato R. Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome. Current molecular medicine. 2011 Jun; 11(4):317-25.
- ↑ McDermott DH, Gao J et al. Chromothriptic Cure of WHIM Syndrome. Cell DOI: http://dx.doi.org/10.1016/j.cell.2015.01.014
- ↑ McDermott DH, Liu Q, Velez D, Lopez L, Anaya-O'Brien S, Ulrick J, Kwatemaa N, Starling J, Fleisher TA, Priel DA, Merideth MA, Giuntoli RL, Evbuomwan MO, Littel P, Marquesen MM, Hilligoss D, DeCastro R, Grimes GJ, Hwang ST, Pittaluga S, Calvo KR, Stratton P, Cowen EW, Kuhns DB, Malech HL, Murphy PM. A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor. Blood. 2014 Apr 10; 123(15):2308-16.(Link to article – subscription may be required.)