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Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants

Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype–phenotype correlations for known pathogenic CXCR4 variants and in vitro response of eac...

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Autores principales: Zmajkovicova, Katarina, Pawar, Sumit, Maier-Munsa, Sabine, Maierhofer, Barbara, Wiest, Ivana, Skerlj, Renato, Taveras, Arthur G., Badarau, Adriana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519442/
https://www.ncbi.nlm.nih.gov/pubmed/36089616
http://dx.doi.org/10.1038/s41435-022-00181-9
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author Zmajkovicova, Katarina
Pawar, Sumit
Maier-Munsa, Sabine
Maierhofer, Barbara
Wiest, Ivana
Skerlj, Renato
Taveras, Arthur G.
Badarau, Adriana
author_facet Zmajkovicova, Katarina
Pawar, Sumit
Maier-Munsa, Sabine
Maierhofer, Barbara
Wiest, Ivana
Skerlj, Renato
Taveras, Arthur G.
Badarau, Adriana
author_sort Zmajkovicova, Katarina
collection PubMed
description Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype–phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4(WHIM) mutations. A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility, and between AKT activation and immunoglobulin A level and CD4(+) T-cell counts. This study is the first to show WHIM syndrome clinical phenotype variability as a function of both CXCR4(WHIM) genotype diversity and associated functional dysregulation. Our findings suggest that CXCR4 internalization may be used to assess the pathogenicity of CXCR4 variants in vitro and also as a potential WHIM-related disease biomarker. The investigational CXCR4 antagonist mavorixafor inhibited CXCL12-dependent signaling in all tested CXCR4-variant cell lines at clinically relevant concentrations.
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spelling pubmed-95194422022-09-30 Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants Zmajkovicova, Katarina Pawar, Sumit Maier-Munsa, Sabine Maierhofer, Barbara Wiest, Ivana Skerlj, Renato Taveras, Arthur G. Badarau, Adriana Genes Immun Article Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype–phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4(WHIM) mutations. A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility, and between AKT activation and immunoglobulin A level and CD4(+) T-cell counts. This study is the first to show WHIM syndrome clinical phenotype variability as a function of both CXCR4(WHIM) genotype diversity and associated functional dysregulation. Our findings suggest that CXCR4 internalization may be used to assess the pathogenicity of CXCR4 variants in vitro and also as a potential WHIM-related disease biomarker. The investigational CXCR4 antagonist mavorixafor inhibited CXCL12-dependent signaling in all tested CXCR4-variant cell lines at clinically relevant concentrations. Nature Publishing Group UK 2022-09-12 2022 /pmc/articles/PMC9519442/ /pubmed/36089616 http://dx.doi.org/10.1038/s41435-022-00181-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zmajkovicova, Katarina
Pawar, Sumit
Maier-Munsa, Sabine
Maierhofer, Barbara
Wiest, Ivana
Skerlj, Renato
Taveras, Arthur G.
Badarau, Adriana
Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title_full Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title_fullStr Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title_full_unstemmed Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title_short Genotype–phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants
title_sort genotype–phenotype correlations in whim syndrome: a systematic characterization of cxcr4(whim) variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519442/
https://www.ncbi.nlm.nih.gov/pubmed/36089616
http://dx.doi.org/10.1038/s41435-022-00181-9
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