Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

Abstract

The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

Serum levels of the IL-6 family of cytokines predict prognosis in renal cell carcinoma (RCC)

“…The results of our study also demonstrate the need for future clinical studies of therapies investigating blockage of gp130 pathways, i.e., bazedoxifene, which blocks p-STAT3 inhibitor [ 39 ], and also combined with other blockers like VEGF-TKIs [ 40 ] to prolong survival in patients with RCC [ 41 ]. However, it should be borne in mind that babies born with a defect gp130 receptor may suffer from extended Stüve-Wiedemann syndrome, which is a serious, often lethal syndrome [ 42 ]. Thus, to block gp130 may have serious side effects, making such treatment impossible.…”

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

“…• vaccine IgG normal • HIES – STAT3-like; • Dermatitis/eczema, eosinophilia, recurrent skin infections, pneumonia, bronchiectasis, pneumatoceles with severe secondary pulmonary aspergillosis, connective tissue defects (scoliosis, face, joints, fractures, palate, tooth retention) • Phenocopies aspects of IL6R and IL11R deficiencies (due to unresponsiveness to these cytokines) Validation • LOF and DN alleles shown by overexpression in GP130 deficient HEK293T cells; • Impaired GP130/STAT3 signaling (mostly downstream of IL-6) in patients’ fibroblasts and leukocytes Table 2 Subtable 5 [ 9 ] IL6ST (complete deficiency; 6 patients, 4 families) AR (LOF) ND (death in utero or in neonatal period occurred for most affected individuals) • Fatal Stuve-Wiedemann-like syndrome; skeletal dysplasia, lung dysfunction, renal abnormalities, thrombocytopenia, dermatitis, eczema • Defective acute phase response • Complete unresponsiveness to IL-6 family cytokines Validation • Complete LOE (for one allele) and LOF for two alleles tested by overexpression in GP130 deficient HEK293T to all cytokines tested of the IL-6 family. • Effects of variants well-characterized, including a partial rescue of patient amniocytes Table 2 Subtable 5 [ 10 , 11 ] FNIP1 (6 patients; 5 families) AR (LOF) Mild T cell lymphocytosis B cell lymphopenia (absent/low; BM block [few immature B cells]) agamma/hypogammaglobulinemia • Early onset recurrent infections (sinopulmonary) • Bronchiectasis • Congenital heart defects (e.g., hypertrophic cardiomyopathy) • Variable neutropenia (severe or intermittent) Crohn disease (one patient) • Developmental delay • Increased AMPK activity Validation • Almost recapitulates the mouse model [ 12 , 13 ] Table 3 Subtable 1 [ 14 , 15 ] PIK3CG (2 patients; 2 families) AR (LOF) • Normal CD4, • ↓ Treg, ↓ CD8 • Normal but ↓ memory B cells • Hypogamma • Intact vaccine responses • Cytopenia/lymphopenia, eosinophilia, lymphadenopathy, splenomegaly, • recurrent infections • HLH-like; ↑ inflammatory markers Validation • ↓ T cell proliferation, activation in vitro • Cellular defects recapitulated in PIK3CG targeted Jurkat T cell line and Pik3cg ko mice Table 3 Subtable 2 [ …”

Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration

“…Therefore, we used AGO2 immunoprecipitation to identify AGO2-bound potential alternative targets of miR-155 (Supplementary Table 2). Three predicted targets, Bdnf, Antxr2 and Il-6st, were chosen for further investigation based on a significant expression change following photooxidative damage in addition to potential roles in neuroprotection [66], angiogenesis [67] and cytokine signalling [68] respectively. These targets were explored in conjunction with the pro-inflammatory cytokine Tnfa and the immunomodulatory Il-10 and Socs1.…”