PSORS2 Is Due to Mutations in CARD14

Abstract

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

The paracaspase MALT1 mediates CARD14‐induced signaling in keratinocytes

“…Recently, several mutations in CARD14 (also known as CARMA2 or Bimp2) were identified in both familial and nonfamilial cases of psoriasis, pinpointing CARD14 as the susceptibility gene of the elusive psoriasis susceptibility locus 2 (PSORS2) in chromosomal region 17q25 [3][4][5][6]. Human CARD14 is a 1,004 amino acid long protein that is characterized by a C-terminal membrane-associated guanylate kinase (MAGUK) domain, which is a structural module composed of a PDZ, SH3, and guanylate kinase-like (GUK) domain.…”

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…An analysis of gene expression data sets indicated significant overlap; CARD10 is expressed in a broad range of tissues, and CARD11, although expressed most highly in the hematopoietic system, is co-expressed with CARD14 in mucosal tissue such as tonsil and tongue papilla. 28 Skin was not included in this analysis, and it now is clear from our work and that of others that both CARD14 and CARD11 are expressed in the epidermis 25 ( Figure 4A). The functional significance of CARD11 expression in the skin is shown by severe dermatitis, erythematous eruptions, and hyperkeratosis, which develop in unmodulated mice that carry an inactivating point mutation in CARD11.…”

“…The related protein CARD14 recently was identified as being expressed in the basal layer of normal skin, which subsequently is up-regulated and altered in distribution in involved skin from patients with psoriasis and pityriasis rubra pilaris. 25,26 Therefore, to ascertain whether CARD11 was present in human skin and cSCC we analyzed expression in vivo using immunohistochemistry and immunofluorescence. A CARD11-specific antibody identified expression in cSCC, with strong positive foci throughout all samples (n Z 38) (Figure 3).…”

“…23 One emerging aspect, which largely was ignored until recently, is the involvement of scaffold proteins that provide a link between membrane receptors and the IKK complex. A direct association between human skin disease and a scaffold protein recently was established with the identification of CARD14 mutations in the common skin disease psoriasis 24,25 and the much rarer condition pityriasis rubra pilaris. 26 Both skin conditions share significant clinical overlap, and molecular characterization has shown common mechanisms driven by mutations in CARD14 that activate NF-kBecentric programs of gene expression.…”

Pityriasis Rubra Pilaris: A Report of Two Cases and Literature Review

“…Th e CARD14 protein is found in many of the body's tissues, but it is particularly abundant in the skin, where it appears to play important roles in regulating infl ammatory reactions. Data obtained recently (28), demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to be caused also by mutations in CARD14 gene (29).…”