Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1
AuthorsStanding, Ariane S.I.
Blundell, Michael P.
Gomes, Sonia Melo
Thrasher, Adrian J.
Brogan, Paul A.
AffiliationUniversity College London
University of Bedfordshire
Great Ormond Street Hospital for Children NHS Foundation Trust
MetadataShow full item record
AbstractThe 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.
CitationStanding ASI, Malinova D, Hong Y, Record J, Moulding D, Blundell M, Nowak K, Jones H, Omoyinmi E, Gilmour KC, Medlar A, Stanescu H, Kleta R, Anderson G, Nanthapisal S, Klein N, Gomes SM, Thrasher AJ, Eleftheriou D, Brogan PA (2017) 'Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1', The Journal of experimental medicine, 214 (1), pp.59-71.
PublisherRockefeller University Press
PubMed Central IDPMC5206503
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-nd/4.0/
- Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β.
- Authors: Kim ML, Chae JJ, Park YH, De Nardo D, Stirzaker RA, Ko HJ, Tye H, Cengia L, DiRago L, Metcalf D, Roberts AW, Kastner DL, Lew AM, Lyras D, Kile BT, Croker BA, Masters SL
- Issue date: 2015 Jun 1
- The Relationship between NALP3 and Autoinflammatory Syndromes.
- Authors: Campbell L, Raheem I, Malemud CJ, Askari AD
- Issue date: 2016 May 13
- Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes.
- Authors: Ozkurede VU, Franchi L
- Issue date: 2012 Mar
- The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation.
- Authors: Manthiram K, Zhou Q, Aksentijevich I, Kastner DL
- Issue date: 2017 Jul 19
- Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome.
- Authors: Jamilloux Y, Lefeuvre L, Magnotti F, Martin A, Benezech S, Allatif O, Penel-Page M, Hentgen V, Sève P, Gerfaud-Valentin M, Duquesne A, Desjonquères M, Laurent A, Rémy-Piccolo V, Cimaz R, Cantarini L, Bourdonnay E, Walzer T, Py BF, Belot A, Henry T
- Issue date: 2018 Jan 1