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

TitleDominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.
Publication TypeJournal Article
Year of Publication2020
AuthorsBéziat, V, Tavernier, SJ, Chen, Y-H, Ma, CS, Materna, M, Laurence, A, Staal, J, Aschenbrenner, D, Roels, L, Worley, L, Claes, K, Gartner, L, Kohn, LA, De Bruyne, M, Schmitz-Abe, K, Charbonnier, L-M, Keles, S, Nammour, J, Vladikine, N, Renkilaraj, MRaj Luxman, Seeleuthner, Y, Migaud, M, Rosain, J, Jeljeli, M, Boisson, B, Van Braeckel, E, Rosenfeld, JA, Dai, H, Burrage, LC, Murdock, DR, Lambrecht, BN, Avettand-Fenoel, V, Vogel, TP, Esther, CR, Haskologlu, S, Dogu, F, Ciznar, P, Boutboul, D, Ouachée-Chardin, M, Amourette, J, Lebras, M-N, Gauvain, C, Tcherakian, C, Ikinciogullari, A, Beyaert, R, Abel, L, Milner, JD, Grimbacher, B, Couderc, L-J, Butte, MJ, Freeman, AF, Catherinot, E, Fieschi, C, Chatila, TA, Tangye, SG, Uhlig, HH, Haerynck, F, Casanova, J-L, Puel, A
Corporate AuthorsUndiagnosed Diseases Network
JournalJ Exp Med
Date Published2020 06 01
KeywordsAdolescent, Alleles, C-Reactive Protein, Cell Membrane, Cells, Cultured, Child, Cytokine Receptor gp130, Cytokines, Female, Fibroblasts, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Job Syndrome, Kinetics, Loss of Function Mutation, Male, Middle Aged, Models, Biological, Mutation, Pedigree, Phenotype, Th2 Cells, Up-Regulation, Young Adult

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.

Alternate JournalJ Exp Med
PubMed ID32207811
PubMed Central IDPMC7971136
Grant ListR01 AI128976 / AI / NIAID NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
R01 AI127564 / AI / NIAID NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
R01 AI085090 / AI / NIAID NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
P01 AI061093 / AI / NIAID NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States