{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T20:35:35Z","timestamp":1769027735283,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sigrid Juselius Foundation"},{"name":"Finnish Cancer Foundation"},{"DOI":"10.13039\/501100006706","name":"Tampere Tuberculosis Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006706","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010600","name":"Tampere University Hospital","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010600","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Janus Kinase (JAK) and Signal Transducers and Activators of Transcription (STAT) pathways regulate a range of biological processes, including immune response and hematopoiesis. While a major research focus has been on somatic human mutations in disease, less is known about the heritability of germline variants and their physiological impact. This study addresses an important issue in population genetics: the context-dependent effects and incomplete penetrance of rare genetic variants in immune pathways. Here we identify the rare JAK3P151R, JAK3R925S, STAT5AV494L, and STAT6Q633H variants in an extended family spanning three generations, integrate in silico analyses and AlphaFold 3 structural predictions, and investigate the immune transcriptomes in probands carrying one or more variants. All four variants are inherited through the germline without any evident clinical or physiological manifestations in the carriers. As individual variants, not all persons carrying a specific variant showed the same immune transcriptome. The presence of activated basal transcriptomes was limited to some, but not all, individuals carrying the above variants. A next step in understanding the role of germline variants will be to understand how and why other factors, including both other germline variants and environmental and developmental factors, influence the likelihood of expression of an activated basal transcriptome.<\/jats:p>","DOI":"10.3390\/ijms27020913","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heritability and Transcriptional Impact of JAK3, STAT5A and STAT6 Variants in a Tyrolean Family"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-5942","authenticated-orcid":false,"given":"Hye Kyung","family":"Lee","sequence":"first","affiliation":[{"name":"National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teemu","family":"Haikarainen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland"},{"name":"Fimlab Laboratories, 33900 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasemin","family":"Caf","sequence":"additional","affiliation":[{"name":"Y2L2Science GmbH, Hauptplatz 4, 6511 Zams, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3883-0715","authenticated-orcid":false,"given":"Priscilla A.","family":"Furth","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludwig","family":"Knabl","sequence":"additional","affiliation":[{"name":"Y2L2Science GmbH, Hauptplatz 4, 6511 Zams, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0747-9512","authenticated-orcid":false,"given":"Olli","family":"Silvennoinen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland"},{"name":"Fimlab Laboratories, 33900 Tampere, Finland"},{"name":"Institute of Biotechnology, Helsinki Institute of Life Science (HiLiFE), University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-9841","authenticated-orcid":false,"given":"Lothar","family":"Hennighausen","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111063","DOI":"10.1016\/j.mce.2020.111063","article-title":"Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2","volume":"519","author":"Hwa","year":"2021","journal-title":"Mol. 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