title: Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1.
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.
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK ariane.standing@ucl.ac.uk.|Institute of Biomedical and Environmental Science and Technology, University of Bedfordshire, Luton LU2 8DL, England, UK.
authors.forename: Ariane S I
authors.identifier: 0000-0002-7178-4274
authors.initials: AS
authors.lastname: Standing
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Dessislava
authors.initials: D
authors.lastname: Malinova
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Ying
authors.identifier: 0000-0001-6909-447X
authors.initials: Y
authors.lastname: Hong
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Julien
authors.identifier: 0000-0003-1138-2916
authors.initials: J
authors.lastname: Record
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Dale
authors.identifier: 0000-0002-1431-7047
authors.initials: D
authors.lastname: Moulding
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Blundell
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Karolin
authors.initials: K
authors.lastname: Nowak
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Jones
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Ebun
authors.initials: E
authors.lastname: Omoyinmi
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, England, UK.
authors.forename: Kimberly C
authors.identifier: 0000-0003-0285-3958
authors.initials: KC
authors.lastname: Gilmour
authors.affiliation: University College London Division of Medicine, London WC1E 6BT, England, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Medlar
authors.affiliation: University College London Division of Medicine, London WC1E 6BT, England, UK.
authors.forename: Horia
authors.initials: H
authors.lastname: Stanescu
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.|University College London Division of Medicine, London WC1E 6BT, England, UK.|Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, England, UK.
authors.forename: Robert
authors.identifier: 0000-0002-0228-8656
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, England, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Sira
authors.identifier: 0000-0003-3196-4657
authors.initials: S
authors.lastname: Nanthapisal
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Sonia Melo
authors.initials: SM
authors.lastname: Gomes
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Despina
authors.initials: D
authors.lastname: Eleftheriou
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Adrian J
authors.identifier: 0000-0002-6097-6115
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: University College London Institute of Child Health, London WC1E 6BT, England, UK.
authors.forename: Paul A
authors.identifier: 0000-0001-6178-6893
authors.initials: PA
authors.lastname: Brogan
mesh_terms: D000199:Actins / Q000378:metabolism; D002648:Child; D005260:Female; D056660:Hereditary Autoinflammatory Diseases / Q000209:etiology / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology / Q000235:genetics*; D058847:Inflammasomes / Q000502:physiology; D020382:Interleukin-18 / Q000097:blood; D008840:Microfilament Proteins / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D010587:Phagocytosis; D013921:Thrombocytopenia / Q000209:etiology / Q000235:genetics*
chemical_list: D000199:Actins; C000589760:IL18 protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D008840:Microfilament Proteins; C118067:WDR1 protein, human