Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome
Loss-of-function (LOF) variants in IL6ST, encoding GP130, can cause hyper-IgE syndrome (HIES). Monoallelic LOF variants in IL6ST 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 IL6ST 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 IL6ST variants. Comprehensive screening of IL6ST 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 782-787) in surface-expressed LOF GP130 led to its accumulation, contributing to the DN effect. The importance of intracellular truncating IL6ST 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 IL6ST variants.
Authors
- Toshio Kubo
- Wei‐Te Lei (ORCID: https://orcid.org/0000-0003-1677-8901)
- Satoshi Okada (ORCID: https://orcid.org/0000-0002-4622-5657)
- Aurélie Cobat (ORCID: https://orcid.org/0000-0001-7209-6257)
- Etsushi Toyofuku
- Kosuke Ashihara
- Takaki Asano (ORCID: https://orcid.org/0000-0003-1424-2433)
- Akimasa Sekine (ORCID: https://orcid.org/0000-0001-8109-8561)
- Yoko Mizoguchi (ORCID: https://orcid.org/0000-0003-3686-9915)
- Shuhei Karakawa (ORCID: https://orcid.org/0000-0003-1853-4759)
- Dusan Bogunovic (ORCID: https://orcid.org/0000-0002-9277-3232)
- Hisao Higo (ORCID: https://orcid.org/0000-0003-4946-0123)
- Vivien Béziat (ORCID: https://orcid.org/0000-0002-4020-824X)
- Miyuki Tsumura (ORCID: https://orcid.org/0000-0002-8272-9588)
- Clément Conil
- Cheng‐Lung Ku (ORCID: https://orcid.org/0000-0002-0643-2256)
- Wenjie Wang (ORCID: https://orcid.org/0000-0002-3199-7785)
- Kohsuke Imai (ORCID: https://orcid.org/0000-0003-2132-8403)
- Kouichi Takeuchi
- Kosuke Noma (ORCID: https://orcid.org/0009-0009-9415-9744)
- Jean-Laurent Casanova (ORCID: https://orcid.org/0000-0002-7782-4169)
Institutions
- Hiroshima University (JP)
- Tokyo Medical and Dental University (JP)
- Howard Hughes Medical Institute (US)
- Inserm (FR)
- St. Marianna University School of Medicine (JP)
- Chang Gung University (TW)
- Université Paris Cité (FR)
- Mackay Memorial Hospital (TW)
- Chang Gung Memorial Hospital (TW)
- Assistance Publique – Hôpitaux de Paris (FR)
- Okayama University Hospital (JP)
- Kanagawa Cardiovascular and Respiratory Center (JP)
- Children's Hospital of Fudan University (CN)
- Institut des Maladies Génétiques Imagine (FR)
- National Defense Medical College (JP)
- The University of Tokyo (JP)
- Columbia University (US)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1172/jci.insight.190065
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science