Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy

Abstract

IL6ST encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through JAK/STAT activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular small monoallelic in-frame deletions of which the most prevalent is IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors (IHCA) but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and shown to be de novo (absent in proband’s parents and siblings) and mosaic (present in approx. 15–40% of cells depending on the tissue studied—blood, urine sediment, hair bulbs, buccal swab). Functional studies were performed in EBV-immortalized patient’s B-cell lymphoblastoid cell line, which carried the variant in approximately 95% of cells. Western blot showed that the patient’s cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3 indicative of IL6 independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1 we speculate that these drugs may be effective in the treatment of our patient’s condition.

Inborn errors of IL-6 family cytokine responses

“…Although many patients do not present with infection susceptibility, there are case reports of mycobacterial disease [ 49 ]. A similar phenotype was seen in a de novo and mosaic IL6ST variant inducing constitutive GP130 cytokine signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy [ 50 •• ]. In STAT3 gain-of-function patients there has been some success in the use of JAK inhibitors to treat the inflammatory disease [ 48 ].…”

Activation of gp130 signaling in T cells drives T H 17-mediated multi-organ autoimmunity

“…The aggressiveness of the Lgp phenotype might explain why to date only one patient case with a mosaic IL6ST GOF mutation has been described ( 22 ). However, a more frequent autoimmune disinhibition syndrome, namely, STAT3 GOF disease, shares numerous clinical characteristics with Lgp mice, such as severe growth retardation, autoimmune cytopenia, lymphoproliferation, and inflammatory interstitial lung disease ( 19 – 21 ).…”

“…Considering the central role of the IL-6 pathway in autoimmunity, it stands to reason that other autoimmune-lymphoproliferative disorders with involvement in this signaling cascade remain without a genetic diagnosis. Only recently, the first pediatric patient harboring a mosaic germline IL6ST mutation presenting with neonatal-onset immunodeficiency and autoinflammation was reported ( 22 ).…”

The Human GP130 Cytokine Receptor and Its Expression—an Atlas and Functional Taxonomy of Genetic Variants

“…Mutations due to loss-of-function of IL6ST variants can lead to a spectrum of distinct clinical phenotypes associated with different GP130-dependent cytokine signaling defects [ 5 ]. In recent years, several genotype-phenotype associations with loss-of-function [ 14 , 23 – 26 ] or gain-of-function in GP130 have been identified [ 27 – 31 ]. As a consequence of the multiple and variable phenotypes and genotypes, a confusing taxonomy, terminology, and nomenclature has developed.…”

“…A child with heterozygous de novo IL6ST p.S187_Y190del variant was recently reported exhibiting neonatal onset immunodeficiency with autoinflammation and dysmorphia [ 31 ]. The p.S187_Y190del variant was previously identified as a constitutively active IL6ST variant in HCA cohorts [ 27 – 30 ].…”