Alt. symbols: PSORS2 | CARMA2 | BIMP2

Approved name: caspase recruitment domain family member 14
Alt. names: psoriasis susceptibility 2, caspase recruitment domain family, member 14

Location: 17q25.3: 80169992 - 80216073 (+)
Gene type: protein_coding, 30 transcripts.

Scores: LoFtool: 0.832000 | pLI: 0.00000000 | LOEUF: 0.995

HGNC: 16446

NCBI: 79092, RefSeq: NG_032778.1

Ensembl: ENSG00000141527.19

LRG_1330 | Status: public

OMIM: 607211

Expression | ProteinAtlas

CARD14 encodes a protein that belongs to both the CARD-CC and membrane-associated guanylate kinase (MAGUK) families of proteins. CARD proteins regulate NF-kappaB signaling in apoptosis, while MAGUK proteins act as molecular scaffolds for the assembly of multiprotein complexes at specific regions in the plasma membrane. Together with CARD11, CARD14 is described to specifically interact with the CARD domain of BCL10, a signaling protein involved in apoptosis that activates NF-kappaB through the IkB kinase complex in response to upstream stimuli (PMID: 11278692). CARD14 is highly expressed in keratinocytes and endothelial cells of the skin (PMID: 25369198). Upon stimulation, CARD14 is phosphorylated by protein kinase C, freed from autoinhibition, and binds to the BCL-10/MALT1 signalosome to promote epidermal NF-κB dependent pro-inflammatory gene expression (PMID: 27939769). Interestingly, CARD14 expression is essentially confined to the basal layer of epidermis in unaffected skin but it is upregulated in the granular layers in the skin of patients with GPP (PMID: 22521418).

Generalized pustular psoriasis (GPP) is an extremely rare type of psoriasis, presenting with pus-filled blisters covering the entire body and often associated with systemic inflammation (PMID: 35060076). Neutrophils isolated from patients with GPP induce greater upregulation of inflammatory cytokines (IL-1β, IL-36G, IL-18, TNF-α) and chemokines in keratinocytes than those from patients without GPP. These neutrophils are then rapidly internalized by keratinocytes, which further amplifie s expression of these inflammatory molecules by activating NF-κB and MAPK signaling (PMID: 30811955). Three monogenic SAIDs are characterized by GPP featuring keratinocyte inflammation: DIRA (IL-1 receptor antagonist deficiency) [OMIM: 612852] due to mutations in IL1RN encoding the IL-1 receptor antagonist (IL-1Ra), DITRA (IL-36 receptor antagonist deficiency) [OMIM: 614204] due to mutations in IL36RN encoding IL-36 receptor antagonist (IL-36Ra), and CAMPS (CARD14-mediated psoriasis). Monoallelic pathogenic variants in CARD14 have been linked to a spectrum of skin inflammatory phenotypes - including psoriasis vulgaris (PV), familial pityriasis rubra pilaris (PRP) [OMIM: 173200] and pustular psoriasis - with variable disease expressivity and penetrance, but without fever or other systemic inflammatory manifestations. These are collectively known as CARD14-mediated psoriasis (CAMPS) [OMIM: 602723]. The centrality of NF-κB activation to the pathophysiology of these disorders explains why patients may respond to treatment with IL-12/23 inhibition by ustekinumab (PMID: 24641799). CAMPS-associated CARD14 mutations are heterozygous GOF missense changes found across all protein domains (with enrichment in the CC domain known to mediate protein oligomerization), leading to a range of amplified NF-κB activities (PMID: 27071417). Mutations in CARD14 gene account for only a small proportion of cases of GPP; unlike for IL36RN, they are more often found in GPP patients with concomitant PV than in those with GPP alone (PMID: 30036598). The most severe reported phenotype in a patient with early-onset GPP arose from a de novo variant disrupting the auto-inhibitory linker domain of CARD14, leading to constitutive activation and the highest level of NF-κB activity seen relative to other CAMPS-associated variants. In contrast, heterozygous dominant-negative mutations that impair downstream NF-κB signaling in keratinocytes have been associated with a severe form of atopic dermatitis (PMID: 30248356). Specific mutations include heterozygous missense mutations (Gly117Ser and Glu138Ala) shown to cause increased NF-kappaB activation and upregulated psoriasis-associated genes (PMID: 22521419). In addition, sequencing of 54 members of a large 5-generation Taiwanese family demonstrated that a heterozygous splice site mutation (c.349+5G>A) segregated with psoriasis. In an accompanying large study of more than 6,000 cases and 4,000 controls, 15 additional rare missense variants (Arg38Cys, Arg62Gln, Glu142Gly, Glu142Lys, Leu150Arg, His171Asn, Asp176His, Arg179His, Val191Leu, Ser200Asn, Asp285Gly, Ile593Asn, Arg682Trp, Gly714Ser and Asp973Gln) were found to be enriched in affected patients vs controls. At least 3 shown to be pathogenic in functional studies were located in the coiled-coil domain. Furthermore, a heterozygous missense mutation (Leu156Pro) and a heterozygous nonsense mutation (c.412_414delGAG) were shown to segregate with disease in three [Load More]