{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T18:57:12Z","timestamp":1779908232458,"version":"3.53.1"},"reference-count":63,"publisher":"American Society for Clinical Investigation","issue":"17","license":[{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"content-version":"vor","delay-in-days":54,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023213","name":"European Society for Immunodeficiencies","doi-asserted-by":"crossref","award":["ERG 2021\/2022"],"award-info":[{"award-number":["ERG 2021\/2022"]}],"id":[{"id":"10.13039\/501100023213","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"crossref","award":["Allocations doctorales 1\u00e8re Ann\u00e9e de th\u00e8se"],"award-info":[{"award-number":["Allocations doctorales 1\u00e8re Ann\u00e9e de th\u00e8se"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-PRTS 2013 \"Immune-Rep\""],"award-info":[{"award-number":["ANR-PRTS 2013 \"Immune-Rep\""]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["E-Rare Joint Transnational Call for Proposals 2015 \"EuroCID\""],"award-info":[{"award-number":["E-Rare Joint Transnational Call for Proposals 2015 \"EuroCID\""]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,3]]},"abstract":"<jats:p>\n                    The ubiquitously expressed small GTPase Ras-related protein 1B (\n                    <jats:italic>RAP1B<\/jats:italic>\n                    ) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline\n                    <jats:italic>RAP1B<\/jats:italic>\n                    variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G&gt;A (p.G12E) in\n                    <jats:italic>RAP1B<\/jats:italic>\n                    . We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient\u2019s hemato-immunological phenotype. Our findings define monoallelic\n                    <jats:italic>RAP1B<\/jats:italic>\n                    gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline\n                    <jats:italic>RAP1B<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.1172\/jci169994","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T14:00:45Z","timestamp":1725285645000},"source":"Crossref","is-referenced-by-count":10,"title":["Somatic RAP1B gain-of-function variant underlies isolated thrombocytopenia and immunodeficiency"],"prefix":"10.1172","volume":"134","author":[{"given":"Marta","family":"Benavides-Nieto","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Paris, France."},{"name":"Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellis\u00e9e Ligue Contre le Cancer, Ligue 2023, INSERM UMR 1163, Paris, France."},{"name":"General Pediatrics\u2013Infectious Diseases and Internal Medicine, H\u00f4pital Robert Debr\u00e9, Assistance Publique-H\u00f4pitaux de Paris (AP-HP) Nord, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6603-2687","authenticated-orcid":true,"given":"Fr\u00e9d\u00e9ric","family":"Adam","sequence":"additional","affiliation":[{"name":"INSERM UMR S 1176, Laboratory for Hemostasis, Inflammation and Thrombosis (HITh), Universit\u00e9 Paris-Saclay, Le Kremlin-Bic\u00eatre, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-7373","authenticated-orcid":true,"given":"Emmanuel","family":"Martin","sequence":"additional","affiliation":[{"name":"Laboratory Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Boussard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Paris, France."},{"name":"Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France."},{"name":"Laboratory Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Lagresle-Peyrou","sequence":"additional","affiliation":[{"name":"Biotherapy Clinical Investigation Center, AP-HP, Paris, France."},{"name":"Laboratory Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Callebaut","sequence":"additional","affiliation":[{"name":"Sorbonne University, Muse\u0301um National d\u2019Histoire Naturelle, UMR CNRS 7590, Institut 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