Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF-κB

Li, Qiaoli; Chung, Hye Jin; Ross, Nicholas; Keller, Matthew; Andrews, Jonathan; Kingman, Joshua; Sarig, Ofer; Fuchs-Telem, Dana; Sprecher, Eli; Uitto, Jouni

doi:10.1038/jid.2015.65

Cited by 30 publications

(57 citation statements)

References 13 publications

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“…It is important to note that our assay for NF‐κB activation levels corresponds very well with other assays that we have previously used to investigate the pathogenic effects of mutant CARD14, including upregulation of NF‐κB targets such as interleukin‐8 by keratinocytes . Consistent with this hypothesis, levels of NF‐κB activation of < 2·5‐fold were also recently described for several pityriasis rubra pilaris CARD14 mutations . However, the c.589G>A (p.Glu197Lys) alteration was recently reported in three of over 1000 German controls, illustrating the problem of determining pathogenicity of rare variants, where the numbers of affected cases are small, and functional assays are not available or indeterminate.…”

Section: Discussionsupporting

confidence: 82%

CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts

et al. 2015

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Summary Background Rare highly penetrant gain of function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs. Objectives To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and expand knowledge of CARD14 variants in the European population. Methods CARD14 coding exons were re-sequenced in psoriasis cases and controls from Tunisia and Europe including included sixteen European cases with generalized pustular psoriasis (GPP). Novel variants seen in cases were evaluated for their effect upon NF-kb signalling. Results Rare variants in CARD14 were significantly enriched in Tunisian cases compared to controls. Three were collectively found in 5% of Tunisian cases and all affected the N terminal region of the protein harbouring its CARD or coiled-coil domain. These variants were: c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-kb activity in a similar manner to previously described psoriasis-associated mutations. p.Arg69Trp led to seven fold down-regulation of NF-kb activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9 which encodes part of the coiled-coil domain. No GPP cases harboured an IL36RN mutation, but one out of 16 GPP cases with a family history of PV harboured a c.1805C>T (p.Ser602Leu) mutation. Conclusions These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.

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Section: Discussionsupporting

confidence: 82%

CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts

et al. 2015

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“…CARD14 GoF mutation causes spontaneous signalosome formation in primary human keratinocytes, which is dependent on a functional CARD domain Consistent with previous reports, CARD14 E138A and DE138 mutants both caused enhanced NF-kB and AP-1 activation in vitro in HEK293 cells compared with wild-type (WT) CARD14, with the E138A mutant showing a more potent response (see Supplementary Figure S1a online) (Afonina et al, 2016;Li et al, 2015). CARD14 E138A and CARD14 DE138 GoF mutants were also overexpressed in primary keratinocytes and HEK293 cells and were observed to interact with endogenous Bcl10 by co-immunoprecipitation ( Figure 1a, and see Supplementary Figure S1b), whereas Bcl10 interaction with CARD14 WT was below detectable levels.…”

Section: Resultssupporting

confidence: 88%

“…Rare autosomal dominant mutations in the gene encoding a keratinocyte scaffold molecule, CARD14 (which maps to the PSORS2 locus) have been associated with a number of psoriatic phenotypes including plaque psoriasis and psoriatic arthritis, generalized pustular psoriasis, and palmoplantar pustular psoriasis, in addition to familial and sporadic cases of the clinically related but rare disease pityriasis rubra pilaris (PRP) (Fuchs-Telem et al, 2012;Has et al, 2016;Hong et al, 2014;Jordan et al, 2012aJordan et al, , 2012bLi et al, 2015;Mossner et al, 2015;Sugiura et al, 2014;Takeichi et al, 2017aTakeichi et al, , 2017b. CARD14 is a proinflammatory signaling molecule whose expression is predominantly restricted to the placenta and keratinocytes of the skin, although CARD14 expression was also reported on CD31-positive endothelial cells (FuchsTelem, 2012; Harden et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Mellett

Meier

Mohanan

et al. 2018

Journal of Investigative Dermatology

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Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-offunction mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14DE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.

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“…At the same time, search for biomarkers, such as genetic alterations linked to development and progression of PRP, would be helpful for diagnosis and prognostication in these challenging cases. 20 …”

Section: Discussionmentioning

confidence: 99%

Epidemiologic, Clinicopathologic, Diagnostic, and Management Challenges of Pityriasis Rubra Pilaris

Ross

Chung

et al. 2016

JAMA Dermatol

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Analysis of CARD14 Polymorphisms in Pityriasis Rubra Pilaris: Activation of NF-κB

Cited by 30 publications

References 13 publications

CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts

CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Epidemiologic, Clinicopathologic, Diagnostic, and Management Challenges of Pityriasis Rubra Pilaris

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