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Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition

Burleigh, A; Moraitis, E; Al Masroori, E; Al-Abadi, E; Hong, Y; Omoyinmi, E; Titheradge, H; ... Eleftheriou, D; + view all (2023) Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition. Frontiers in Immunology , 14 , Article 1287258. 10.3389/fimmu.2023.1287258. Green open access

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Abstract

ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/β signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.

Type: Article
Title: Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2023.1287258
Publisher version: https://doi.org/10.3389/fimmu.2023.1287258
Language: English
Additional information: Copyright © 2023 Burleigh, Moraitis, Al Masroori, Al-Abadi, Hong, Omoyinmi, Titheradge, Stals, Jones, Gait, Jayarajan, Di, Sebire, Solman, Ogboli, Welch, Sudarsanam, Wacogne, Price-Kuehne, Jensen, Brogan and Eleftheriou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: ISG15, ISG15 deficiency, Janus kinase inhibition, baricitinib, interferon, interferonopathy, microdeletion, whole exome sequencing, Humans, Ubiquitins, Cytokines, Interferons, Ubiquitin Thiolesterase
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10184601
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