Activating CARD14 Mutations Are Associated with Generalized Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis Vulgaris

Abstract

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). 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.

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.…”

Pustulöse Psoriasis

“…Ist die Funktion des Antagonisten durch die genetische Variation vermindert, so überwiegen die proinflammatorischen Einflüsse der Agonisten. Zudem wurden bestimmte Variationen im CARD14-Gen identifiziert, die mit GPP assoziiert sind [4]. Die Prävalenz der GPP variiert und liegt bei etwa 1-9/1 Mio.…”

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

“…There was a reduction of Bcl10 expression observed in the presence of all three CARD14 constructs in HEK293 cells (see Supplementary Figure S1b) and a decrease of CARD14 mutant expression in primary keratinocytes (Figure 1a). Previously, it has been suggested that CARD14 mutants associated with psoriasis are less soluble than WT CARD14 (Berki et al, 2015). Additionally, it has been previously described that Bcl10 forms oligomeric structures that can be nucleated by CARD11 (Qiao et al, 2013).…”