{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:18:58Z","timestamp":1781716738453,"version":"3.54.5"},"reference-count":21,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001779","name":"Monash University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001779","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Inborn errors of immunity (IEI) affecting B-cell receptor signaling cause predominantly antibody deficiency (PAD) with varying degrees of severity. Recently, four heterozygous variants in\n                      <jats:italic>SYK<\/jats:italic>\n                      were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to unravel the genetic and functional cause of PAD in a 43-year-old female presenting with hypogammaglobulinemia, congenital heart disease and pulmonary hypertension requiring lung transplantation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patient gDNA was subjected to whole-exome and Sanger sequencing. Blood B- and T-cell subsets, as well as tonic and antigen-receptor induced expression levels of phosphorylated-SYK, phosphorylated-ribosomal S6 and phosphorylated p38 were evaluated by flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A novel heterozygous missense\n                      <jats:italic>SYK<\/jats:italic>\n                      variant was identified, mutating a residue in the protein kinase domain (c.1769G\u2009&gt;\u2009A; p.R590Q), which is highly conserved across vertebrates. While total B- and T-cell numbers were within the normal range, the patient had reduced unswitched and class-switched memory B-cell numbers. Resting B cells from the patient demonstrated enhanced autophosphorylation of SYK, and tonic and ligand-induced phospho-S6 levels. Spontaneous SYK autophosphorylation, S6 and p38 phosphorylation were recapitulated in a pre-clinical cell model, i.e. expression of the SYK R590Q variant in HEK293T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified a novel gain-of-function variant in\n                      <jats:italic>SYK<\/jats:italic>\n                      to underlie hypogammaglobulinemia and atypical autoinflammatory disease. Flowcytometric screening for phospho-S6 in lymphocytes of IEI patients can guide genetic diagnosis of B-cell signaling abnormalities.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10875-025-01950-7","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T08:38:24Z","timestamp":1760949504000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient"],"prefix":"10.1007","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0240-4370","authenticated-orcid":false,"given":"Emily S. 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Syk and pTyr\u2019d: signaling through the B cell antigen receptor. Biochim Biophys Acta. 2009;1793(7):1115\u201327.","journal-title":"Biochim Biophys Acta"},{"issue":"7","key":"1950_CR2","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.186.7.1027","volume":"186","author":"MT Crowley","year":"1997","unstructured":"Crowley MT, et al. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J Exp Med. 1997;186(7):1027\u201339.","journal-title":"J Exp Med"},{"issue":"47","key":"1950_CR3","doi-asserted-by":"publisher","first-page":"32650","DOI":"10.1074\/jbc.M806340200","volume":"283","author":"E Tsang","year":"2008","unstructured":"Tsang E, et al. Molecular mechanism of the Syk activation switch. 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The backgrounds for figures 1 and 4 were mistakenly changed to black.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"None.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"147"}}