WHIM syndrome

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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.

WHIM syndrome[1] is caused by gain-of-function mutations affecting CXCR4. This is characterized by an autosomal dominant inheritance of:

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)[2] . The CXCR4 antagonist plerixafor is in development as possible treatment[3].