Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

Yin-Huai Chen; Diane B Zastrow; Riley D Metcalfe; Lisa Gartner; Freia Krause; Craig J Morton; Shruti Marwaha; Laure Fresard; Yong Huang; Chunli Zhao; Colleen McCormack; David Bick; Elizabeth A Worthey; Christine M Eng; Jessica Gold; Undiagnosed Diseases Network; Stephen B Montgomery; Paul G Fisher; Euan A Ashley; Matthew T Wheeler; Michael W Parker; Veerabahu Shanmugasundaram; Tracy L Putoczki; Dirk Schmidt-Arras; Arian Laurence; Jonathan A Bernstein; Michael D W Griffin; Holm H Uhlig

doi:10.1016/j.jaci.2021.02.044

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome

J Allergy Clin Immunol. 2021 Aug;148(2):585-598. doi: 10.1016/j.jaci.2021.02.044. Epub 2021 Mar 23.

Authors

Yin-Huai Chen¹, Diane B Zastrow², Riley D Metcalfe³, Lisa Gartner¹, Freia Krause⁴, Craig J Morton³, Shruti Marwaha², Laure Fresard⁵, Yong Huang², Chunli Zhao², Colleen McCormack², David Bick⁶, Elizabeth A Worthey⁶, Christine M Eng⁷, Jessica Gold⁸, Undiagnosed Diseases Network⁹, Stephen B Montgomery¹⁰, Paul G Fisher¹¹, Euan A Ashley¹², Matthew T Wheeler¹³, Michael W Parker¹⁴, Veerabahu Shanmugasundaram¹⁵, Tracy L Putoczki¹⁶, Dirk Schmidt-Arras⁴, Arian Laurence¹⁷, Jonathan A Bernstein¹⁸, Michael D W Griffin³, Holm H Uhlig¹⁹

Affiliations

¹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
² Center for Undiagnosed Diseases, Stanford University, Stanford, Calif.
³ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia.
⁴ Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany.
⁵ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Pathology, Stanford School of Medicine, Stanford, Calif.
⁶ Hudson Alpha Institute for Biotechnology, Huntsville, Ala.
⁷ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Baylor College of Medicine, Houston, Tex.
⁸ Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
⁹ National Institutes of Health Undiagnosed Diseases Network, Common Fund, Office of the Director and the National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
¹⁰ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Pathology, Stanford School of Medicine, Stanford, Calif; Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
¹¹ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Neurology, Stanford University School of Medicine, Stanford University, Stanford, Calif.
¹² Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Genetics, Stanford University School of Medicine, Stanford, Calif.
¹³ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Medicine, Stanford School of Medicine, Stanford, Calif.
¹⁴ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia; St Vincent's Institute of Medical Research, Melbourne, Australia.
¹⁵ Bristol-Myers Squibb, Cambridge, Mass.
¹⁶ Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
¹⁷ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom. Electronic address: arian.laurence@ndm.ox.ac.uk.
¹⁸ Center for Undiagnosed Diseases, Stanford University, Stanford, Calif; Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
¹⁹ Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom.

PMID: 33771552
DOI: 10.1016/j.jaci.2021.02.044

Abstract

Background: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling.

Objective: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants.

Methods: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed.

Results: We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome.

Conclusion: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

Keywords: GP130; IL-11; IL-6; IL6ST; LIF; STAT3; hyper-IgE syndrome.

Publication types

Case Reports
Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Child
Cytokine Receptor gp130* / chemistry
Cytokine Receptor gp130* / genetics
Cytokine Receptor gp130* / immunology
Cytokines / genetics
Cytokines / immunology
Exome Sequencing
Genes, Recessive
Humans
Job Syndrome* / genetics
Job Syndrome* / immunology
Male
Molecular Dynamics Simulation*
Mutation, Missense*
RNA-Seq
Signal Transduction / genetics
Signal Transduction / immunology

Substances

Cytokines
IL6ST protein, human
Cytokine Receptor gp130

Abstract

Publication types

MeSH terms

Substances

Grants and funding