PXD016341

PXD016341 is an original dataset announced via ProteomeXchange.

Title	Cold-induced urticarial autoinflammatoy syndrome related to factor XII activation
Description	Early onset urticarial rash with systemic inflammatory symptoms are hallmarks of hereditary autoinflammatory diseases caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). However, in many cases genetic tests are negative, suggesting the existence of unrecognized genetic variants. Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identified a novel substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Occurrence of the mutation segregated with disease status. Functional studies revealed fragmentation and spontaneous activation of FXII in patient plasma and supernatant of HEK293 cells transfected with recombinant W268R-mutated proteins. Furthermore, we observed contact system activation with reduced plasma prekallikrein and profound cleavage of high molecular weight kininogen, representing bradykinin production. As a local source of FXII, skin and blood neutrophils were identified. Interleukin-1ß (IL-1ß) was upregulated in lesional skin and in mononuclear donor cells exposed to recombinant mutant proteins. In accordance with these findings, treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduced disease activity in patients. Thus, we identified anovel autoinflammatory syndrome characterized by a substitution in the F12 gene resulting in activation of the contact system and cytokine-mediated inflammation.
HostingRepository	PRIDE
AnnounceDate	2020-01-10
AnnouncementXML	Submission_2020-02-17_02:27:04.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marieluise Kirchner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-19 05:37:57	ID requested
1	2020-01-10 06:05:17	announced
⏵ 2	2020-02-17 02:27:06	announced	2020-02-17: Updated publication reference for PubMed record(s): 31924766.

Scheffel J, Mahnke NA, Hofman ZLM, Maat S, Wu J, Bonnekoh H, Pengelly RJ, Ennis S, Holloway JW, Kirchner M, Mertins P, Church MK, Maurer M, Maas C, Krause K, Cold-induced urticarial autoinflammatory syndrome related to factor XII activation. Nat Commun, 11(1):179(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: Factor XII, activation, cleavage

Karoline Krause
contact affiliation	Charite Universitaetsmedizin Berlin, Department of Dermatology and Allergy; Autoinflammation Reference Center (ARC2)
contact email	karoline.krause@charite.de
lab head
Marieluise Kirchner
contact affiliation	Max Delbrueck Center, Berlin
contact email	marieluise.kirchner@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016341
     1. Label: PRIDE project
     2. Name: Cold-induced urticarial autoinflammatoy syndrome related to factor XII activation