{"id":24138,"date":"2025-02-10T12:00:00","date_gmt":"2025-02-10T11:00:00","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/02\/10\/pulmonary-aspergillosis-and-low-hies-score-in-a-family-with-stat3-n-terminal-domain-mutation\/"},"modified":"2025-02-10T12:00:00","modified_gmt":"2025-02-10T11:00:00","slug":"pulmonary-aspergillosis-and-low-hies-score-in-a-family-with-stat3-n-terminal-domain-mutation","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/02\/10\/pulmonary-aspergillosis-and-low-hies-score-in-a-family-with-stat3-n-terminal-domain-mutation\/","title":{"rendered":"Pulmonary Aspergillosis and Low HIES Score in a Family with STAT3 N-Terminal Domain Mutation"},"content":{"rendered":"<div>\n<p><b>J Clin Immunol<\/b>. 2025 Feb 10;45(1):73. doi: 10.1007\/s10875-025-01867-1.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of STAT3 NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers&#8217; peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers&#8217; PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37* STAT3 mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39928202\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_campaign=journals&amp;utm_content=8102137&amp;ff=20250210124951&amp;v=2.18.0.post9+e462414\">39928202<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1007\/s10875-025-01867-1\">10.1007\/s10875-025-01867-1<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>J Clin Immunol. 2025 Feb 10;45(1):73. doi: 10.1007\/s10875-025-01867-1. ABSTRACT Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) &#8230; <a title=\"Pulmonary Aspergillosis and Low HIES Score in a Family with STAT3 N-Terminal Domain Mutation\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/02\/10\/pulmonary-aspergillosis-and-low-hies-score-in-a-family-with-stat3-n-terminal-domain-mutation\/\" aria-label=\"Read more about Pulmonary Aspergillosis and Low HIES Score in a Family with STAT3 N-Terminal Domain Mutation\">Read more<\/a><\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[69,42],"tags":[],"class_list":["post-24138","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\/24138","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"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=24138"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/24138\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=24138"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=24138"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=24138"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}