{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:27:20Z","timestamp":1789381640215,"version":"build-2803163510"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministery of Health","award":["GR-2013-02356521"],"award-info":[{"award-number":["GR-2013-02356521"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,8]]},"abstract":"<jats:p>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 3 patients presenting neutropenia and myelokathexis, but normal lymphocyte count and immunoglobulin levels, carrying what we believe to be 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 in comparison with R334X mutation. The L317fsX3 mutation impairs CXCR4 downregulation and \u03b2-arrestin recruitment in response to CXCL12 and reduces other signaling events \u2014 including ERK1\/2 phosphorylation, calcium mobilization, and chemotaxis \u2014 all processes that 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.<\/jats:p>","DOI":"10.1172\/jci.insight.145688","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T14:01:14Z","timestamp":1678197674000},"source":"Crossref","is-referenced-by-count":19,"title":["Reduced G protein signaling despite impaired internalization and \u03b2-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome"],"prefix":"10.1172","volume":"8","author":[{"given":"Rajesh","family":"Kumar","sequence":"first","affiliation":[{"name":"\u201cAngelo Nocivelli\u201d Institute for Molecular Medicine, University of Brescia, Brescia, Italy."},{"name":"Rheumatology and Clinical Immunology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili, Brescia, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Milanesi","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy."},{"name":"IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5659-8377","authenticated-orcid":true,"given":"Martyna","family":"Szpakowska","sequence":"additional","affiliation":[{"name":"Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Dotta","sequence":"additional","affiliation":[{"name":"\u201cAngelo Nocivelli\u201d Institute for Molecular Medicine, University of Brescia, Brescia, Italy."},{"name":"Department of Pediatrics, ASST Spedali Civili, Brescia, Italy."},{"name":"Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili, Brescia, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7143-6229","authenticated-orcid":true,"given":"Dario","family":"Di Silvestre","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies\u2013National Research Council (ITB-CNR), Segrate, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Trotta","sequence":"additional","affiliation":[{"name":"Microenvironment Molecular Targets, Istituto Nazionale Tumori\u2013IRCCS\u2013Fondazione G. 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