A biallelic mutation in <i>IL6ST</i> encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

Schwerd, Tobias; Twigg, Stephen R.F.; Aschenbrenner, Dominik; Manrique, Santiago; Miller, Kerry A.; Taylor, Indira B.; Capitani, Melania; McGowan, Simon J.; Sweeney, Elizabeth; Weber, Astrid; Chen, L; Bowness, Paul; Riordan, Andrew; Cant, Andrew J.; Freeman, Alexandra F.; Milner, Joshua D.; Holland, Steven M.; Frede, Natalie; Müller, Miryam; Schmidt-Arras, Dirk; Grimbacher, Bodo; Wall, Steven A.; Jones, E Y; Wilkie, Andrew O.M.; Uhlig, Holm H.

doi:10.1084/jem.20161810

Cited by 173 publications

(157 citation statements)

References 62 publications

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“…The present study confirms the disease-causing role of this gene. The more severe phenotype in the patient described by Schwerd et al [2017] compared to that in the present study is probably due to the bi-allelic mutation in their case, which resulted in complete abolition of protein production and function.…”

Section: Discussioncontrasting

confidence: 52%

“…The deleted region in chromosome 5q11 contains 45 genes, amongst which IL6ST is identified as the probable gene related to immunodeficiency due to its established role in immune responses. The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL-6), ciliary neurotrophic factor, leukaemia inhibitory factor, and oncostatin M. This protein functions as a part of the cytokine receptor complex [Tanaka et al, 2014;Schwerd et al, 2017]. It has also been called the B-cell stimulatory factor 2 (BSF-2), based on the ability to induce differentiation of activated B cells into antibody-producing cells, especially IgG producing IL-21 [Hirano et al, 1986;Ma et al ., 2012].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recurrent infections have been previously described in 4 patients with 5q11.2 microdeletion syndrome, and all 4 were haploinsufficient for this gene , thus substantiating this hypothesis. Furthermore, Schwerd et al [2017] presented a patient with recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, and an impaired acute-phase response. The patient was found to have a homozygous loss-of-function mutation of IL6ST (encoding gp130 p.N404Y).…”

Section: Discussionmentioning

confidence: 99%

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Extending the Phenotype and Identification of a Novel Candidate Gene for Immunodeficiency in 5q11 Microdeletion Syndrome

et al. 2018

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Array CGH has led to the delineation of innumerable microdeletion syndromes. We present a patient with a 7-Mb deletion at 5q11.2 with previously unreported features, such as immunodeficiency, asymmetry of hands and feet, joint laxity, and agenesis of corpus callosum. The clinical features of this patient are compared with 13 patients reported previously. A common critical region (CCR) of 1.4 Mb (54-55.4 Mb) is defined in all cases including the present one. Of the 14 genes present in CCR, IL6ST is proposed to be the candidate gene for immunodeficiency observed in some of these patients. IL6ST encodes gp130, a signal transduction protein for various interleukins and cytokines. It is involved in the generation of both T and B lymphocytes as well as the production of acute-phase reactants. Microdeletion 5q11.2 should be considered as a recognisable syndrome based on the common phenotype and the novel features described.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Extending the Phenotype and Identification of a Novel Candidate Gene for Immunodeficiency in 5q11 Microdeletion Syndrome

et al. 2018

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“…Patients with inborn errors of receptors or cytokines upstream from STAT3 display overlapping syndromes. Indeed, memory B-cell deficiency has been detected in IL-6ST-deficient patients and in IL-21R-deficient patients, who also have low frequencies of central memory CD8 + T cells, Tfh cells, and NKT cells (15, 18, 13, 19, 17, 12). …”

Section: Introductionmentioning

confidence: 99%

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

et al. 2018

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Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

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“…Therefore, calvarial mesenchyme has been proposed to have dual osteoblast and chondrogenic identity. The finding of mutations in interleukin genes in syndromes featuring immunodeficiency, failed molar tooth eruption, and craniosynostosis also suggests the involvement of bone-resorbing osteoclasts in maintenance of suture patency [Nieminen et al, 2011;Keupp et al, 2013;Schwerd et al, 2017]. Therefore, several key bone cell types are potentially relevant targets for treatment of craniosynostosis.…”

mentioning

confidence: 99%

An FDA-Approved Drug Screen for Compounds Influencing Craniofacial Skeletal Development and Craniosynostosis

Seda¹,

Geerlings²,

Lim³

et al. 2018

Mol Syndromol

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Neural crest stem/progenitor cells (NCSCs) populate a variety of tissues, and their dysregulation is implicated in several human diseases including craniosynostosis and neuroblastoma. We hypothesised that small molecules that inhibit NCSC induction or differentiation may represent potential therapeutically relevant drugs in these disorders. We screened 640 FDA-approved compounds currently in clinical use for other conditions to identify those which disrupt development of NCSC-derived skeletal elements that form the zebrafish jaw. In the primary screen, we used heterozygous transgenic sox10:gfp zebrafish to directly visualise NCSC-derived jaw cartilage. We noted partial toxicity of this transgene in relation to jaw patterning, suggesting that our primary screen was sensitised for NCSC defects, and we confirmed 10 novel, 4 previously reported, and 2 functional analogue drug hits in wild-type embryos. Of these drugs, 9/14 and 7/14, respectively, are known to target pathways implicated in osteoarthritis pathogenesis or to cause reduced bone mineral density/increased fracture risk as side effects in patients treated for other conditions, suggesting that our screen enriched for pathways targeting skeletal tissue homeostasis. We selected one drug that inhibited NCSC induction and one drug that inhibits bone mineralisation for further detailed analyses which reflect our initial hypotheses. These drugs were leflunomide and cyclosporin A, respectively, and their functional analogues, teriflunomide and FK506 (tacrolimus). We identified their critical developmental windows of activity, showing that the severity of defects observed related to the timing, duration, and dose of treatment. While leflunomide has previously been shown to inhibit NCSC induction, we demonstrate additional later roles in cartilage remodelling. Both drugs altered expression of extracellular matrix metalloproteinases. As proof-of-concept, we also tested drug treatment of disease-relevant mammalian cells. While leflunomide treatment inhibited the viability of several human NCSC-derived neuroblastoma cell lines coincident with altered expression of genes involved in ribosome biogenesis and transcription, FK506 enhanced murine calvarial osteoblast differentiation and prevented fusion of the coronal suture in calvarial explants taken from Crouzon syndrome mice.

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A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis

Abstract: Schwerd et al. report a novel homozygous missense substitution in the cytokine co-receptor GP130 encoded by IL6ST. This is associated with defective IL-6, IL-11, OSM, and IL-27 signaling and causes immunodeficiency and skeletal abnormalities with similarities to STAT3 hyper-IgE syndrome.

Cited by 173 publications

References 62 publications

Extending the Phenotype and Identification of a Novel Candidate Gene for Immunodeficiency in 5q11 Microdeletion Syndrome

Extending the Phenotype and Identification of a Novel Candidate Gene for Immunodeficiency in 5q11 Microdeletion Syndrome

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

An FDA-Approved Drug Screen for Compounds Influencing Craniofacial Skeletal Development and Craniosynostosis

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