Dataset Information

Cold-induced urticarial autoinflammatoy syndrome related to factor XII activation

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Blood

DISEASE(S): Urticaria

SUBMITTER: Marieluise Kirchner

LAB HEAD: Karoline Krause

PROVIDER: PXD016341 | Pride | 2010-01-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	FX12.fasta	Fasta
	Leia_20190802_MK_FX_Mutant_1.raw	Raw
	Leia_20190802_MK_FX_Mutant_2.raw	Raw
	Leia_20190802_MK_FX_Mutant_3.raw	Raw
	Leia_20190802_MK_FX_Mutant_4.raw	Raw

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Publications

Cold-induced urticarial autoinflammatory syndrome related to factor XII activation.

Scheffel Jörg J Mahnke Niklas A NA Hofman Zonne L M ZLM Maat Steven de S Wu Jim J Bonnekoh Hanna H Pengelly Reuben J RJ Ennis Sarah S Holloway John W JW Kirchner Marieluise M Mertins Philipp P Church Martin K MK Maurer Marcus M Maas Coen C Krause Karoline K

Nature communications 20200110 1

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). 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 identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleav ...[more]

PMID: 31924766

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