Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due...

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Published in:The Journal of experimental medicine 2020-06, Vol.217 (6)
Main Authors: Béziat, Vivien, Tavernier, Simon J, Chen, Yin-Huai, Ma, Cindy S, Materna, Marie, Laurence, Arian, Staal, Jens, Aschenbrenner, Dominik, Roels, Lisa, Worley, Lisa, Claes, Kathleen, Gartner, Lisa, Kohn, Lisa A, De Bruyne, Marieke, Schmitz-Abe, Klaus, Charbonnier, Louis-Marie, Keles, Sevgi, Nammour, Justine, Vladikine, Natasha, Maglorius Renkilaraj, Majistor Raj Luxman, Seeleuthner, Yoann, Migaud, Mélanie, Rosain, Jérémie, Jeljeli, Mohamed, Boisson, Bertrand, Van Braeckel, Eva, Rosenfeld, Jill A, Dai, Hongzheng, Burrage, Lindsay C, Murdock, David R, Lambrecht, Bart N, Avettand-Fenoel, Véronique, Vogel, Tiphanie P, Esther, Charles R, Haskologlu, Sule, Dogu, Figen, Ciznar, Peter, Boutboul, David, Ouachée-Chardin, Marie, Amourette, Jean, Lebras, Marie-Noëlle, Gauvain, Clément, Tcherakian, Colas, Ikinciogullari, Aydan, Beyaert, Rudi, Abel, Laurent, Milner, Joshua D, Grimbacher, Bodo, Couderc, Louis-Jean, Butte, Manish J, Freeman, Alexandra F, Catherinot, Émilie, Fieschi, Claire, Chatila, Talal A, Tangye, Stuart G, Uhlig, Holm H, Haerynck, Filomeen, Casanova, Jean-Laurent, Puel, Anne
Format: Article
Language:English
Subjects:
Adolescent
Alleles
C-Reactive Protein - metabolism
Cell Membrane - metabolism
Cells, Cultured
Child
Cytokine Receptor gp130 - deficiency
Cytokine Receptor gp130 - genetics
Cytokines - biosynthesis
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Genes, Dominant
Genetics, Population
HEK293 Cells
Human Disease Genetics
Humans
Immunodeficiency
Immunology
Job Syndrome - blood
Job Syndrome - diagnostic imaging
Job Syndrome - genetics
Job Syndrome - immunology
Kinetics
Life Sciences
Loss of Function Mutation - genetics
Male
Middle Aged
Models, Biological
Mutation - genetics
Pedigree
Phenotype
Th2 Cells - metabolism
Up-Regulation
Young Adult
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Summary:Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20191804