Figure 8.
Hierarchical organization of monogenic disorders in the IL-6 cytokine family pathway. Schematic of IL-6 family receptor complexes and associated human genetic disorders. OSM signals via LIFR/GP130 (type I) and OSMRβ/GP130 (type II), while IL-31 signals through OSMRβ/IL-31RA and IL-6 through IL-6Rα/GP130. The lower panel maps cytokine, receptor, and co-receptor defects to inheritance patterns and clinical phenotypes. Complete IL6ST and LIFR deficiency cause severe multisystem developmental disease; partial or dominant-negative IL6ST variants result in hyper-IgE–like phenotypes; OSM deficiency causes bone marrow failure; biallelic OSMR LOF, defined in this study, causes a PAD; and dominant OSMR or IL31RA variants cause cutaneous amyloidosis. The gradient reflects a proposed hierarchy of phenotypic breadth according to the position of the affected gene within the signaling cascade. AD, autosomal dominant; AR, autosomal recessive; DN, dominant negative; GP130, glycoprotein 130; JAK, Janus Kinase; LIFR, leukemia inhibitory factor receptor; sOSMR, soluble OSMRβ; STAT, signal transducer and transactivator. Refer to the image caption for details. The diagram shows the signaling pathways for IL-6, Type 1 OSM, Type 2 OSM, and IL-31 through their respective receptors and co-receptors. The upper section illustrates the receptor complexes for IL-6, Type 1 OSM, Type 2 OSM, and IL-31, showing the interactions with GP130, LIFR, OSMR, and IL-31RA. The lower section maps cytokine, receptor, and co-receptor defects to inheritance patterns and clinical phenotypes. It highlights the effects of complete IL6ST and LIFR deficiency, partial or dominant-negative IL6ST variants, OSM deficiency, biallelic OSMR LOF, and dominant OSMR or IL31RA variants. The gradient reflects the proposed hierarchy of phenotypic breadth according to the position of the affected gene within the signaling cascade.

Hierarchical organization of monogenic disorders in the IL-6 cytokine family pathway. Schematic of IL-6 family receptor complexes and associated human genetic disorders. OSM signals via LIFR/GP130 (type I) and OSMRβ/GP130 (type II), while IL-31 signals through OSMRβ/IL-31RA and IL-6 through IL-6Rα/GP130. The lower panel maps cytokine, receptor, and co-receptor defects to inheritance patterns and clinical phenotypes. Complete IL6ST and LIFR deficiency cause severe multisystem developmental disease; partial or dominant-negative IL6ST variants result in hyper-IgE–like phenotypes; OSM deficiency causes bone marrow failure; biallelic OSMR LOF, defined in this study, causes a PAD; and dominant OSMR or IL31RA variants cause cutaneous amyloidosis. The gradient reflects a proposed hierarchy of phenotypic breadth according to the position of the affected gene within the signaling cascade. AD, autosomal dominant; AR, autosomal recessive; DN, dominant negative; GP130, glycoprotein 130; JAK, Janus Kinase; LIFR, leukemia inhibitory factor receptor; sOSMR, soluble OSMRβ; STAT, signal transducer and transactivator.

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