{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:06:03Z","timestamp":1790280363647,"version":"4.1.0"},"reference-count":32,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Society for the Promotion of Science (JSPS) KAKENHI, the Japan Agency for Medical Research and Development (AMED), JSPS Program for Forming Japan\u2019s Peak Research Universities","award":["22H03041,22KK0113,23K14979,22K15921,JP23ek0109623,JP22ek0109480"],"award-info":[{"award-number":["22H03041,22KK0113,23K14979,22K15921,JP23ek0109623,JP22ek0109480"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>\n                    Loss-of-function (LOF) variants in\n                    <jats:italic>IL6ST<\/jats:italic>\n                    , encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in\n                    <jats:italic>IL6ST<\/jats:italic>\n                    lead to HIES when located in the intracellular domain downstream of box 1\/2 and upstream of the STAT3 phosphorylation sites and the recycling motif, due to their dominant negative (DN) activity. In this region, 2 previously unreported\n                    <jats:italic>IL6ST<\/jats:italic>\n                    variants, p.K702Sfs7* and p.Y759Wfs26*, were identified in 2 families with autosomal dominant (AD) HIES. Both variants were LOF and exhibited DN effects, leading to the accumulation of mutant GP130 on the cell surface. The p.K702Sfs7* mutation was the most upstream N-terminal mutation linked to HIES caused by heterozygous\n                    <jats:italic>IL6ST<\/jats:italic>\n                    variants. Comprehensive screening of\n                    <jats:italic>IL6ST<\/jats:italic>\n                    mutants revealed that most premature terminations downstream of amino acid F641, at the end of the transmembrane domain, resulted in LOF and DN effects via GP130 accumulation on the cell surface. The absence of the recycling motif (positions 782\u2013787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating\n                    <jats:italic>IL6ST<\/jats:italic>\n                    variants can possibly be predicted based on the location of the premature stop codon. GP130 accumulation on the cell surface is a characteristic and potentially diagnostic finding in patients with HIES with heterozygous\n                    <jats:italic>IL6ST<\/jats:italic>\n                    variants.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.190065","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T12:00:29Z","timestamp":1750161629000},"source":"Crossref","is-referenced-by-count":1,"title":["Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome"],"prefix":"10.1172","volume":"10","author":[{"given":"Kosuke","family":"Ashihara","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaki","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan."},{"name":"Department of Radiation Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Noma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Tsumura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Te","family":"Lei","sequence":"additional","affiliation":[{"name":"Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan."},{"name":"Division of Immunology, Rheumatology, and Allergy, Department of Pediatrics, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Higo","sequence":"additional","affiliation":[{"name":"Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, 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France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etsushi","family":"Toyofuku","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan."},{"name":"Department of Rheumatology and Allergology, St. Marianna University School of Medicine, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akimasa","family":"Sekine","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohsuke","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan."},{"name":"Department of Pediatrics, National Defense Medical College, Saitama, 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