Rare, highly penetrant, gain-of-function, dominantly acting mutations within the human caspase recruitment domain family, member 14 (CARD14) gene lead to the development of PS and psoriatic arthritis (PSA) (a familial p.G117S and de-novo p.E138A alteration).
Although dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, loss-of-function mutations in the same gene are associated with a severe variant of AD.
Consistently, many psoriasis susceptibility genes encode the TRAF6 signaling players, such as ACT1 (<i>TRAF3IP2</i>), A20 (<i>TNFAIP3</i>), ABIN1 (<i>TNIP1</i>), IL-36Ra (<i>IL36RN</i>), IkappaBzeta (<i>NFKBIZ</i>), and CARD14.
It is known that particular caspase recruitment domain family member 14 (CARD14) gene mutations are associated with familial PRP and certain forms of psoriasis.
Similarly, mutations in the CARD14 gene have been linked to pustular types of psoriasis and familiar cases of pityriasis rubra pilaris; however, there are no reports associating mutations in the CARD14 gene with AGEP.
Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.
Rare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown.Mellett et al. generated mice harboring the patient-derived gain-of-function Card14ΔE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis.
Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.
Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus <i>PSORS2</i>, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders.
Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-κB activation in keratinocytes in psoriatic initiation.
In conclusion, our findings identify a new mechanism through which the ability of CARMA2 to activate NF-κB is regulated, which could have significant implications for our understanding of why mutations of this protein trigger human psoriasis.
This suggests that the difference in molecular charge and the resulting change in molecular interaction around the N-terminal end of the coiled-coil region of CARD14 molecule do not determine the phenotypic differences between psoriasis and PRP.
Collectively, our findings demonstrate a novel role for MALT1 in CARD14-induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis.
In summary, this paper describes a family with CARD14-related psoriasis and discusses the possible influence of the specific haplotypes on intra-familial variation in the clinical phenotype of the disease.
In contrast with wild-type CARD14, CARD14(E138A) and CARD14(G117S) psoriasis mutants interacted constitutively with BCL10 and MALT1, and triggered BCL10- and MALT1-dependent activation of NF-κB in keratinocytes.
Genome-wide association studies have found the single nucleotide polymorphism (SNP) c.C2458T, at the caspase recruitment domain family member 14 (CARD14) gene, to be associated with psoriasis.
CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP).
These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.