WHIM Syndrome: Report of a Novel Familial CXCR4V340fs Gain-of-function Mutation with a Milder Phenotype

Abstract

Abstract WHIM syndrome is a rare, autosomal dominant inborn errors of immunity characterized by warts, hypogammaglobulinemia, infection, and myelokathexis. It is caused mainly by heterozygous mutations at the C-terminus of the C-X-C chemokine receptor type 4 (CXCR4) gene. Here, we report a Chinese family of four harboring a novel mutation in the C-terminal domain of CXCR4 (c.1016_1017dupCT), which caused a frameshift at codon V340, resulting in an extension of 14 amino acids (p.V340L fs*27). All four patients had recurrent respiratory infections and neutropenia, but no hypogammaglobulinemia. However, the number of naïve T cells and B cell subsets was significantly lower than normal. Compared with a patient harboring hotspot mutation CXCR4R334X, those with the CXCR4V340fs mutation had a milder clinical and immunological phenotype. Accordingly, and similar to the CXCR4R334X mutation, the novel frameshift mutation CXCR4V340fs resulted in impaired receptor downregulation in patients’ PBMCs, and in HEK293T cells transfected with mutant plasmids, thereby increasing the amplitude and duration of p-AKT and p-ERK1/2 signaling after CXCL12 stimulation. Thus, we describe a novel pathogenic CXCR4 mutation causing familial WHIM syndrome.