The combinatorial biology of IL6 family cytokines – lessons from Mendelian GP130 defects.

Cytokines of the IL6 family of cytokines impact virtually on all cells of mammalians. Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 cause a variety of clinical phenotypes and disorders. This can be explained by common variants in the IL6ST locus that affect IL6ST gene expression as well as rare genetic variants that impact on the combinatorial biology of the GP130 receptor-coreceptor-complex. We recently described a taxonomy of rare genetic variants including (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome.

In this seminar, we discuss a novel class of genetic variants in GP130 that are associated with defective assembly of the receptor-JAK complex causing abnormal GP130 surface expression and intracellular accumulation.

The example of IL6ST illustrates a complex one gene-multiple phenotype model were variants in one gene impact signalling of several members of the IL6 cytokine family. The set of Mendelian disorders provide new inside into the cell biology of GP130 dependent cytokine receptor signalling.