Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actinregulatory gene WDR1

Ariane S.I. Standing*, Dessislava Malinova, Ying Hong, Julien Record, Dale Moulding, Michael P. Blundell, Karolin Nowak, Hannah Jones, Ebun Omoyinmi, Kimberly C. Gilmour, Alan Medlar, Horia Stanescu, Robert Kleta, Glenn Anderson, Sira Nanthapisal, Sonia Melo Gomes, Nigel Klein, Despina Eleftheriou, Adrian J. Thrasher, Paul A. Brogan

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

The importance of actin dynamics in the activation of the inflammasome is becoming increasingly apparent. IL-1β, which is activated by the inflammasome, is known to be central to the pathogenesis of many monogenic autoinflammatory diseases. However, evidence from an autoinflammatory murine model indicates that IL-18, the other cytokine triggered by inflammasome activity, is important in its own right. In this model, autoinflammation was caused by mutation in the actin regulatory gene WDR1. We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia. We found impaired actin dynamics in patient immune cells. Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture. We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity. We transfected HEK293T cells with pyrin and wild-type and mutated WDR1. Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly. We have extended the findings from the mouse model to highlight the importance of WDR1 and actin regulation in the activation of the inflammasome, and in human autoinflammation.

Original languageEnglish
Pages (from-to)59-71
Number of pages13
JournalJournal of Experimental Medicine
Volume214
Issue number1
DOIs
Publication statusPublished - Jan 2017
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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