Alternative titles; symbols
HGNC Approved Gene Symbol: CARD14
SNOMEDCT: 3755001; ICD10CM: L44.0; ICD9CM: 696.4;
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:80,170,030-80,209,331 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Pityriasis rubra pilaris | 173200 | Autosomal dominant | 3 |
| Psoriasis 2 | 602723 | Autosomal dominant | 3 |
The caspase recruitment domain (CARD) is a protein module that consists of 6 or 7 antiparallel alpha helices. It participates in apoptosis signaling through highly specific protein-protein homophilic interactions. CARDs induce nuclear factor kappa-B (NFKB; 164011) activity through the IKK (e.g., IKBKB, 603258) complex. CARD9 (607212), CARD10 (607209), CARD11 (607210), and CARD14 interact with BCL10 (603517) and are involved in NFKB signaling complexes. Except for CARD9, these CARD proteins are members of the membrane-associated guanylate kinase (MAGUK) family (summary by Bertin et al., 2001).
By database searching for CARD family members, Bertin et al. (2001) identified CARD14. The deduced 1,004-amino acid protein contains an N-terminal CARD domain that is 52% identical to that of CARD11, a central coiled-coil domain, and a C-terminal tripartite structure composed of a PDZ domain, an SH3 domain, and a GUK domain. Northern blot analysis revealed expression of a 4.4-kb transcript in placenta. In contrast, CARD11 was expressed in thymus, spleen, liver, and peripheral blood leukocytes, as well as in hemopoietic cancer cell lines.
By database searching for CARD proteins with high similarity to, and therefore a greater likelihood of interacting with, BCL10, Gaide et al. (2001) identified CARD11, CARD14, and CARD10, which they termed CARMA1, CARMA2, and CARMA3, respectively.
Jordan et al. (2012) stained normal and psoriatic skin samples with a polyclonal antibody specific to the coiled-coil domain of CARD14 and observed staining of basal keratinocytes in normal and uninvolved skin, with decreased expression in the upper layers of the skin, including the granular layer.
Fuchs-Telem et al. (2012) performed comparative quantitative analysis of CARD14 expression in 22 different tissues and found that CARD14 RNA levels are 5 times higher in the skin than in any other human tissue.
Using luciferase reporter analysis, Bertin et al. (2001) showed that CARD14 induces NFKB activity through IKKG (IKBKG; 300248) or IKKB and that this induction requires the N terminus of CARD14. Deletion of the C-terminal domains of CARD14 resulted in enhanced NFKB activity, suggesting a negative regulatory function. Mammalian 2-hybrid and coprecipitation analyses indicated that CARD domains of CARD11 and CARD14 interact with the CARD of BCL10. Fluorescence microscopy demonstrated a cytoplasmic colocalization of CARD14 with BCL10. Functional analysis showed that CARD11 and CARD14 both phosphorylate BCL10 in a CARD-dependent manner.
Susceptibility to Psoriasis 2
In affected members of 2 families with psoriasis (PSORS2; 602723) and 1 sporadic patient, Jordan et al. (2012) identified heterozygosity for 1 splice site and 2 missense mutations in the CARD14 gene (607211.0001-607211.0003). Transfection studies in the HEK001 keratinocyte cell line showed that the mutations caused enhanced NFKB (164011) activation and upregulation of a subset of psoriasis-associated genes compared to wildtype.
To determine whether additional rare variants in the CARD14 gene predispose to psoriasis, Jordan et al. (2012) screened 7 psoriasis cohorts involving more than 6,000 cases and 4,000 controls. Fifteen additional rare missense variants were identified and found to be enriched in cases compared to controls (burden test, p = 0.0015; variable threshold test, p = 0.0053), with pathogenic variants located primarily in the coiled-coil domain of CARD14. Two of the rare variants were not found in controls and manifested as overtly causative (607211.0004 and 607211.0005). Metaanalysis revealed an association between psoriasis and SNP rs11652075 (R820W; p = 2.1 x 10(-6)); evidence for association increased in 2 cohorts of European ancestry when the PSORS1 (177900) variant HLA-Cw*0602 (rs10484554) was included as a covariate, suggesting a genetic connection between PSORS1 and PSORS2. In addition, Jordan et al. (2012) observed a wide range of phenotypes even among individuals with the same CARD14 substitution, indicating that genetic background and/or environmental factors may be involved.
Pityriasis Rubra Pilaris
In 3 families with autosomal dominant pityriasis rubra pilaris mapping to chromosome 17q25 (PRP; 173200), Fuchs-Telem et al. (2012) identified heterozygosity for a missense mutation and a nonsense mutation in the CARD14 gene (607211.0006 and 607211.0007, respectively) that segregated with disease in each family. In 2 patients from a fourth family with PRP, they identified a heterozygous splice site mutation (607211.0008). Analysis of skin biopsies from PRP patients revealed that CARD14 immunostaining was stronger in PRP-affected skin than in normal skin and was localized up to the granular layers, whereas CARD14 staining was mostly restricted to the lower layers of the normal epidermis. In addition, there was a significantly higher percentage of activated-p65 (see 164014)-positive nuclei in skin of PRP-affected individuals compared to controls.
Using CRISPR-Cas9 technology, Wang et al. (2018) generated mice heterozygous for the glu138-to-ala (E138A; 607211.0003) mutation in the Card14 gene and also obtained mice heterozygous for a deletion of gln136 (Q136) in the Card14 gene. Mice heterozygous for E138A exhibited significantly lower survival rate than mice heterozygous for the Q136 deletion. Both types of mutant mice developed spontaneous psoriasis-like phenotype. Introduction of the Q136 deletion on an Il17a (603149) -/- background partially reduced ear thickness compared with Q136-deleted Il17a +/+ mice, indicating that Il17a was involved in development of psoriasis. Further analysis confirmed that T cells were the main source of Il7a in Card14-mutant mice. Card14 expression was higher in primary keratinocytes compared with T and B cells, and expression of the Card14 mutations in nonhematopoietic cells, likely keratinocytes, was necessary for initiation of psoriasis in mice. Coexpression of the Card14 mutations with NF-kappa-B (see 164011)-dependent luciferase reporters in 293T cells resulted in constitutive activation of NF-kappa-B, and NF-kappa-B activation was required for Card14 mutation-initiated development of psoriasis. The Card14 mutations disrupted the intramolecular interaction between the coiled-coil domain and linker domain of the protein and exposed the aggregation sites for Card14 oligomerization, leading to constitutive activation of NF-kappa-B signaling. The authors also generated Card14 -/- mice and found that Card14 deletion attenuated skin inflammation in response to imiquimod treatment. Comparison of primary keratinocytes of Card14 -/- and wildtype mice identified Card14 as a signaling component interacting with the Act1 (TRAF3IP2; 607043)-Traf6 (602355) complex to regulate Il17a signaling.
In a large 3-generation family of European ancestry with psoriasis and psoriatic arthritis (PSORS2; 602723), previously studied by Tomfohrde et al. (1994) (family PS1), Jordan et al. (2012) identified heterozygosity for a 349G-A transition in exon 3 of the CARD14 gene, resulting in a gly117-to-ser (G117S) substitution at a highly conserved residue involved in the splice donor sequence of exon 3. The mutation segregated with disease in the family, and it was not found in the 1000 Genomes Project or dbSNP (build 130) databases, or in 8 previously exome-sequenced HapMap individuals. In vitro splicing assays showed that this mutation leads to the use of a cryptic splice donor site 66 base pairs from the start of intron 3, causing the insertion of 22 amino acids into the CARD14 peptide between exons 3 and 4. Analysis of RNA from involved skin from an affected family member showed that 47% of CARD14 transcripts were wildtype, 12% harbored the 349A allele but with correct splicing between exons 3 and 4, 9% included the 66-bp intronic insertion, and 17% were due to skipping of exon 3; similar ratios of wildtype and mutant transcripts were seen after PCR-based cloning and sequencing of cDNA spanning exons 2 to 4. Luciferase reporter assays demonstrated a 3- to 4-fold increase in activation of NFKB (164011) compared to wildtype. Transfected HEK001 keratinocytes showed increased upregulation of psoriasis-associated genes with mutant compared to wildtype CARD14: 1.9-fold greater than wildtype for CCL20 (601960) and 1.6-fold for IL8 (146930). Jordan et al. (2012) also identified a variant in the SLC26A11 gene (610117) on chromosome 17q25 that segregated with disease in family PS1; the authors stated that further investigation would be required to determine whether or not that variant contributes independently to psoriasis or psoriatic arthritis.
Jordan et al. (2012) identified the G117S mutation in 3 additional psoriasis patients: a woman who was diagnosed at 10 years of age with psoriasis and developed psoriatic arthritis at age 20, and a mother and daughter who were diagnosed with psoriasis at age 65 years and 32 years, respectively. The mutation was also detected in a male control for whom additional data regarding age, ethnicity, and family history were unavailable. None of these individuals carried the SLC26A11 mutation that was identified in family PS1, providing evidence that these variants can arise independently.
Korber et al. (2013) reported a patient who had psoriasis vulgaris from age 10 years and who developed generalized pustular psoriasis at age 55. The patient was heterozygous for a missense mutation in the IL36RN gene (S113L; 605507.0002), and Korber et al. (2013) also identified compound heterozygosity for G117S and another missense mutation in the CARD14 gene. The authors suggested that the G117S mutation was responsible for the long-standing psoriasis vulgaris, whereas the additional IL36RN mutation might have induced the development of pustular psoriasis.
In a large 5-generation Taiwanese family with psoriasis (PSORS2; 602723), previously studied by Hwu et al. (2005), Jordan et al. (2012) identified heterozygosity for a 349+5G-A transition in intron 3 of the CARD14 gene, resulting in use of a cryptic splice donor site 66 basepairs from the start of intron 3 and causing the insertion of 22 amino acids into the CARD14 peptide between exons 3 and 4. The mutation segregated with disease in the family, and it was not found in the 1000 Genomes Project or dbSNP (build 130) databases, or in 8 previously exome-sequenced HapMap individuals. Jordan et al. (2012) noted that a mutation in the ZNF750 gene (610336.0002) had previously been found to segregate with the disease in this family by Yang et al. (2008).
In a 3-year-old Haitian girl with early-onset generalized pustular psoriasis (PSORS2; 602723), Jordan et al. (2012) identified heterozygosity for a de novo 413A-C transversion in exon 4 of the CARD14 gene, resulting in a glu138-to-ala (E138A) substitution at a highly conserved residue in the coiled-coil domain. The mutation was not found in the 1000 Genomes Project or dbSNP (build 130) databases, or in 8 previously exome-sequenced HapMap individuals. Luciferase reporter assays demonstrated a 7- to 9-fold increase in activation of NFKB (164011) compared to wildtype. Transfected HEK001 keratinocytes showed increased upregulation of psoriasis-associated genes with mutant compared to wildtype CARD14: 7.2-fold greater than wildtype for CCL20 (601960), 4.6-fold for IL8 (146930), 4.1-fold for SOD2 (147460), and 1.8-fold for IL36G (605542). In addition, upregulation of these transcripts in primary keratinocytes from the patient was confirmed.
In a Caucasian man diagnosed at age 42 years with psoriasis (PSORS2; 602723), Jordan et al. (2012) identified heterozygosity for a 424G-A transition in the CARD14 gene, resulting in a glu142-to-lys (E142K) substitution in the coiled-coil domain. The mutation was not found in 1,874 controls. Transfection studies in the keratinocyte cell line HEK001 revealed that the E142K mutant increased NFKB (164011) activation 4-fold more than did wildtype. The patient's disease responded well to UV light and a topical mixture of corticosteroid and a vitamin D analog.
In a Caucasian man diagnosed with psoriasis (PSORS2; 602723) in infancy and whose father also had psoriasis, Jordan et al. (2012) identified heterozygosity for a 425A-G transition in the CARD14 gene, resulting in a glu142-to-gly (E142G) substitution in the coiled-coil domain. The mutation was not found in 2,848 controls. Transfection studies in the keratinocyte cell line HEK001 revealed that the E142G mutant increased NFKB (164011) activation 5-fold more than did wildtype. The patient experienced a partial remission of psoriasis with methotrexate treatment.
In affected members from 2 unrelated 3-generation families segregating autosomal dominant pityriasis rubra pilaris (PRP; 173200), Fuchs-Telem et al. (2012) identified heterozygosity for a 467T-C transition in exon 4 of the CARD14 gene, resulting in a leu156-to-pro (L156P) substitution at a highly conserved residue. The mutation, which segregated with disease in both families and was not found in 100 population-matched controls or in major public databases, was detected on the background of distinct haplotypes in each family, suggesting spontaneously recurrent mutational events rather than a founder effect.
In affected members of a 3-generation family segregating autosomal dominant pityriasis rubra pilaris (PRP; 173200), Fuchs-Telem et al. (2012) identified heterozygosity for a 3-bp deletion (412delGAG) in exon 4 of the CARD14 gene, resulting in deletion of a highly conserved residue (glu138del). The mutation segregated with disease in the family and was not found in 100 population-matched controls or in major public databases.
In affected members of a 3-generation family segregating autosomal dominant pityriasis rubra pilaris (PRP; 173200), Fuchs-Telem et al. (2012) identified heterozygosity for a G-A transition in intron 3 (349+1G-A) of the CARD14 gene that abolishes the consensus donor splice site and results in use of a cryptic splice site, generating an aberrant splice variant with the insertion of an extra 66 basepairs originating from intron 3. The mutation was not found in 100 population-matched controls or in major public databases.
Bertin, J., Wang, L., Guo, Y., Jacobson, M. D., Poyet, J.-L., Srinivasula, S. M., Merriam, S., DiStefano, P. S., Alnemri, E. S. CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa-B. J. Biol. Chem. 276: 11877-11882, 2001. [PubMed: 11278692] [Full Text: https://doi.org/10.1074/jbc.M010512200]
Fuchs-Telem, D., Sarig, O., van Steensel, M. A. M., Isakov, O., Israeli, S., Nousbeck, J., Richard, K., Winnepenninckx, V., Vernooij, M., Shomron, N., Uitto, J., Fleckman, P., Richard, G., Sprecher, E. Familial pityriasis rubra pilaris is caused by mutations in CARD14. Am. J. Hum. Genet. 91: 163-170, 2012. [PubMed: 22703878] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.010]
Gaide, O., Martinon, F., Micheau, O., Bonnet, D., Thome, M., Tschopp, J. Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappa-B activation. FEBS Lett. 496: 121-127, 2001. [PubMed: 11356195] [Full Text: https://doi.org/10.1016/s0014-5793(01)02414-0]
Hwu, W.-L., Yang, C.-F., Fann, C. S. J., Chen, C.-L., Tsai, T.-F., Chien, Y.-H., Chiang, S.-C., Chen, C.-H., Hung, S.-I., Wu, J.-Y., Chen, Y.-T. Mapping of psoriasis to 17q terminus. (Letter) J. Med. Genet. 42: 152-158, 2005. [PubMed: 15689454] [Full Text: https://doi.org/10.1136/jmg.2004.018564]
Jordan, C. T., Cao, L., Roberson, E. D. O., Duan, S., Helms, C. A., Nair, R. P., Duffin, K. C., Stuart, P. E., Goldgar, D., Hayashi, G., Olfson, E. H., Feng, B.-J., and 14 others. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappa-B, in psoriasis. Am. J. Hum. Genet. 90: 796-808, 2012. [PubMed: 22521419] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.013]
Jordan, C. T., Cao, L., Roberson, E. D. O., Pierson, K. C., Yang, C.-F., Joyce, C. E., Ryan, C., Duan, S., Helms, C. A., Liu, Y., Chen, Y., McBride, A. A., Hwu, W.-L., Wu, J.-Y., Chen, Y.-T., Menter, A., Goldbach-Mansky, R., Lowes, M. A., Bowcock, A. M. PSORS2 is due to mutations in CARD14. Am. J. Hum. Genet. 90: 784-795, 2012. [PubMed: 22521418] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.012]
Korber, A., Mossner, R., Renner, R., Sticht, H., Wilsmann-Theis, D., Schulz, P., Sticherling, M., Traupe, H., Huffmeier, U. Mutations in IL36RN in patients with generalized pustular psoriasis. (Letter) J. Invest. Derm. 133: 2634-2637, 2013. [PubMed: 23648549] [Full Text: https://doi.org/10.1038/jid.2013.214]
Tomfohrde, J., Silverman, A., Barnes, R., Fernandez-Vina, M. A., Young, M., Lory, D., Morris, L., Wuepper, K. D., Stastny, P., Menter, A., Bowcock, A. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science 264: 1141-1145, 1994. [PubMed: 8178173] [Full Text: https://doi.org/10.1126/science.8178173]
Wang, M., Zhang, S., Zheng, G., Huang, J., Songyang, Z., Zhao, X., Lin, X. Gain-of-function mutation of Card14 leads to spontaneous psoriasis-like skin inflammation through enhanced keratinocyte response to IL-17A. Immunity 49: 66-79, 2018. [PubMed: 29980436] [Full Text: https://doi.org/10.1016/j.immuni.2018.05.012]
Yang, C.-F., Hwu, W.-L., Yang, L.-C., Chung, W.-H., Chien, Y-H., Hung C.-C., Chen, H.-C., Tsai, P.-J., Fann, C. S. J., Liao F., Chen Y.-T. A promoter sequence variant of ZNF750 is linked with familial psoriasis. J. Invest. Derm. 128: 1662-1668, 2008. [PubMed: 18256691] [Full Text: https://doi.org/10.1038/jid.2008.1]