{"id":46290,"date":"2025-10-20T12:00:00","date_gmt":"2025-10-20T10:00:00","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/10\/20\/novel-syk-variant-causes-enhanced-syk-autophosphorylation-and-pi3k-activation-in-an-antibody-deficient-patient\/"},"modified":"2025-10-20T12:00:00","modified_gmt":"2025-10-20T10:00:00","slug":"novel-syk-variant-causes-enhanced-syk-autophosphorylation-and-pi3k-activation-in-an-antibody-deficient-patient","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/10\/20\/novel-syk-variant-causes-enhanced-syk-autophosphorylation-and-pi3k-activation-in-an-antibody-deficient-patient\/","title":{"rendered":"Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient"},"content":{"rendered":"<div>\n<p><b>J Clin Immunol<\/b>. 2025 Oct 20;45(1):147. doi: 10.1007\/s10875-025-01950-7.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>BACKGROUND: 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 SYK were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma.<\/p>\n<p>OBJECTIVE: 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.<\/p>\n<p>METHODS: 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.<\/p>\n<p>RESULTS: A novel heterozygous missense SYK variant was identified, mutating a residue in the protein kinase domain (c.1769G &gt; A; 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.<\/p>\n<p>CONCLUSIONS: We identified a novel gain-of-function variant in SYK 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.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/41114848\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_campaign=journals&amp;utm_content=8102137&amp;ff=20251020134919&amp;v=2.18.0.post9+e462414\">41114848<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1007\/s10875-025-01950-7\">10.1007\/s10875-025-01950-7<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>J Clin Immunol. 2025 Oct 20;45(1):147. doi: 10.1007\/s10875-025-01950-7. ABSTRACT BACKGROUND: 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 SYK were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma. OBJECTIVE: We aimed to unravel the genetic &#8230; <a title=\"Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/10\/20\/novel-syk-variant-causes-enhanced-syk-autophosphorylation-and-pi3k-activation-in-an-antibody-deficient-patient\/\" aria-label=\"Read more about Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[69,42],"tags":[],"class_list":["post-46290","post","type-post","status-publish","format-standard","hentry","category-journal-of-clinical-immunology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/46290","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=46290"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/46290\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=46290"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=46290"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=46290"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}