IRCCS Humanitas Research Hospital & Humanitas University
Published November 5, 2020 | Version v2
Dataset Restricted

Dataset related to article "Reduced G protein signaling despite impaired internalization and β-arrestin recruitment in patients carrying a novel CXCR4Leu317fsX3 mutation causing WHIM syndrome"

Authors/Creators

  • 1. Institute for Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy; Rheumatology and Clinical Immunology, ASST Spedali Civili, Brescia, Italy.
  • 2. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy.
  • 3. Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg.
  • 4. Department of Pediatrics and Institute for Molecular Medicine "Angelo Nocivelli", ASST Spedali Civili, Brescia, Italy
  • 5. National Research Council - Institute for Biomedical Technologies
  • 6. Istituto Nazionale Tumori IRCCS Fondazione Pascale
  • 7. Institute for Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy
  • 8. Department of Clinical Hematology, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
  • 9. Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy
  • 10. IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
  • 11. Institute for Molecular Medicine "Angelo Nocivelli", University of Brescia, Brescia, Italy.
  • 12. ROR icon IRCCS Humanitas Research Hospital
  • 13. Humanitas University
  • 14. Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.

Description

This record contains raw data related to article  "IReduced G protein signaling despite impaired internalization and β-arrestin recruitment in patients carrying a novel CXCR4Leu317fsX3 mutation causing WHIM syndrome"

WHIM syndrome is an inherited immune disorder caused by an autosomal dominant heterozygous mutation in CXCR4. The disease is characterized by neutropenia/leukopenia (secondary to retention of mature neutrophils in bone marrow), recurrent bacterial infections, treatment-refractory warts, and hypogammaglobulinemia. All mutations reported in WHIM patients lead to the truncations in the C-terminal domain of CXCR4, R334X being the most frequent. This defect prevents receptor internalization, and enhances both calcium mobilization and ERK phosphorylation, resulting in increased chemotaxis in response to the unique ligand CXCL12. Here, we describe three patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying a novel Leu317fsX3 mutation in CXCR4, leading to a complete truncation of its intracellular tail. The analysis of the L317fsX3 mutation in cells derived from patients and in vitro cellular models reveals unique signaling features when compared to R334X mutation. L317fsX3 mutation impairs CXCR4 downregulation and β-arrestin recruitment in response to CXCL12 and reduces other signaling events including ERK1/2 phosphorylation, calcium mobilization and chemotaxis, all processes, which are typically enhanced in cells carrying the R334X mutation. Our findings suggest that overall, the L317fsX3 mutation may be causative of a form of WHIM syndrome not associated with an augmented CXCR4 response to CXCL12.

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