WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4

Abstract

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder sonamed because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-offunction mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G 3 A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4 R334X , the most common truncation mutation in WHIM syndrome, CXCR4 E343K mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however,

Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors

“…In most cases, WHIM syndrome is associated with the dominant inheritance of variants of the chemokine receptor CXCR4 with mutations in the last 10 to 19 C-terminal amino acids. [1][2][3][4] These mutations lead to a hyperfunctional receptor with impaired internalization and increased responsiveness to CXCL12. 2,5 Dysfunctional CXCR4-mediated signaling is a common manifestation in WHIM patients, even in cases in which the disorder is not genetically associated with CXCR4 mutations.…”

A Waldenström-macroglobulinaemia és betegségre szabott kezelése

“…A CXCR4 fenti mutációit WHIM-mutációknak is szokás nevezni, mert hasonló csíravonalbeli mutáció-kat írtak le WHIM-szindrómában (autoszomális domináns módon megjelenő szemölcsök, hypogammaglobulinaemia, infekciók és myelocathexis). Ebben a szindrómában a CXCR4-mutációk hatására bekövetkező folyamatos jelátvitel a lymphocyták fejlődési károsodásá-hoz, valamint a neutrophil sejtek csontvelői retenciójá-hoz (myelocathexis) vezet [16]. WM-ben a CXCR4-mutációk jellemzően szubklonálisak, és egy betegben többféle CXCR4-mutáns szubklón is jelen lehet, ám csaknem minden esetben MYD88-mutációhoz másodla-gosan társult formában [17].…”

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome

“…20 One WHIM patient has been identified as lacking CXCR4 mutations but displaying a decreased expression of GRK3, which normally mediates CXCR4 desensitization. 6 In addition, Liu et al reported a novel missense, nontruncating C-terminus mutation (E343K) that is associated with the impaired CXCR4 downregulation and reduced CXCR4 desensitization, although to a smaller extent than other reported mutations 17 ( Table 2). Moreover, a heterozygous 5-bp deletion (nucleotides 986-990) CXCR4 (L329fs) frameshift variant resulting in substitution of the final 24 predicted amino acids of the carboxy-terminal domain of the receptor with 12 missense amino acids has been recently described Figure 1.…”

“…The CXCR4 intracellular tail mediates its negative regulation through G-protein-coupled receptor kinase (GRK)-mediated phosphorylation and b-arrestin-mediated internalization 2,3,14,17 (Table 2). Consequently, the mutated receptor displays an impaired ligand-dependent downregulation and prolonged responses of CXCR4 mutants to CXCL12 (ie, gain of function causing an excessive accumulation of mature neutrophils, lymphocytes, and monocytes in the bone marrow and accounting for the symptoms of the disease 3,5,6,18,19 ).…”