Thanks to the technique of sequencing the genome (precisely its coding part, the exome), the mutation responsible for the development of the disease, described as IL6ST Tyr186_Tyr190del, was identified. The results of the work of our combined research teams have been published in the prestigious Human Molecular Genetics, and their importance has been highlighted by the publisher by including the result of the study on the cover of the current issue of the journal.
The IL6ST gene encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family. The GP130 protein mutation uncontrollably stimulates JAK and STAT proteins, which regulate a number of important cellular functions. Somatic IL6ST mutations, in particular, small monoallelic in-frame deletions, of which the most prevalent is IL6ST Ser187_Tyr190del, are a known cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described.
Further studies showed that the mutated patient's cells are characterized by stimulating STAT3 signaling proteins. With these findings, the doctors hope that the novel inhibitors of the JAK/STAT signaling pathway- ruxolitinib or tofacitinib-can be used to treat the new disease syndrome.
Authors: Anna Materna-Kiryluk - Polish Registry of Congenital Malformations, Chair and Department of Medical Genetics, Poznan University of Medical Sciences; Agnieszka Pollak - Department of Medical Genetics, Warsaw Medical University, Karol Gawalski - Department of Immunology, Medical University of Warsaw, Aleksandra Szczawinska-Poplonyk - Department of Pediatric Pneumonology, Allergology and Clinical Immunology, Institute of Pediatrics, Poznan University of Medical Sciences, Zuzanna Rydzynska - Department of Immunology, Medical University of Warsaw, Anna Sosnowska - Department of Immunology, Medical University of Warsaw, Bożena Cukrowska - Laboratory of Immunology, Department of Pathology, The Children’s Memorial Health Institute, Piotr Gasperowicz - Department of Medical Genetics, Warsaw Medical University, Ewa Konopka - Laboratory of Immunology, Department of Pathology, The Children’s Memorial Health Institute, Barbara Pietrucha - Department of Clinical Immunology, The Children’s Memorial Health Institute, Tomasz M. Grzywa - Department of Immunology, Medical University of Warsaw, The Doctoral School of the Medical University of Warsaw, Magdalena Banaszak-Ziemska - Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, Marek Niedziela - Department of Pediatric Endocrinology and Rheumatology, Institute of Pediatrics, Poznan University of Medical Sciences, Jolanta Skalska-Sadowska - Department of Pediatric Oncology, Hematology and Transplantology University of Medical Sciences, Piotr Stawinski - Department of Medical Genetics, Warsaw Medical University, Dariusz Śladowski - Department of Transplantology and Central Tissue Bank, Centre for Biostructure, Medical University of Warsaw, Dominika Nowis - Laboratory of Experimental Medicine, Medical University of Warsaw, Rafal Ploski - Department of Medical Genetics, Warsaw Medical University.
