Familial Pityriasis Rubra Pilaris Is Caused by Mutations in CARD14

Abstract

Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14.

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).…”

“…Mutations in the CARD14 gene on chromosome 17q25 (28), which encodes a group of interactive protein known as nuclear factor-kappa B (NF-kB), have been found in some families. NF-kB regulates the activity of multiple genes, including genes that control immune responses and infl ammatory reactions; CARD14 gene mutations enhance the activation of NF-kB signaling pathway which causes an aberrant infl ammatory response.…”

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

“…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).…”

“…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. 24e26 Caspase recruitment domain (CARD)-containing proteins are conserved across many species and are characterized by the presence of different functional domains shared between family members.…”

Genetics research: jumping into the deep end of the pool

“…By means of computational investigation, scientists attempt to link particular genetic composition, or changes thereof, to functional outcomes or phenotypes . The advent of genome sequencing allows for the : (i) identification of genetic diseases (Walsh et al, 2010 ;Fuchs-Telem et al, 2012) ; (ii) mapping of cancerous tissue (Ley et al, 2008) ; and (iii) profiling of pathogen infections , to name a few. A decade ago, fewer than 100 genetic disease-causative genes were identified.…”