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. 2012 May 4;90(5):784-95.
doi: 10.1016/j.ajhg.2012.03.012. Epub 2012 Apr 19.

PSORS2 is due to mutations in CARD14

Catherine T Jordan  1 , Li Cao, Elisha D O Roberson, Katherine C Pierson, Chi-Fan Yang, Cailin E Joyce, Caitriona Ryan, Shenghui Duan, Cynthia A Helms, Yin Liu, Yongqing Chen, Alison A McBride, Wuh-Liang Hwu, Jer-Yuarn Wu, Yuan-Tsong Chen, Alan Menter, Raphaela Goldbach-Mansky, Michelle A Lowes, Anne M Bowcock
Affiliations

PSORS2 is due to mutations in CARD14

Catherine T Jordan et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Positional Cloning of PSORS2 and Mutations Segregating in Linked Families (A) Location of PSORS2 showing polymorphic microsatellites D17S784 and D17S982 and the locations of CARD14 and SLC26A11 and familial mutations. The following abbreviation is used: SGSH, N-sulfoglucosamine sulfohydrolase (MIM 605270). (B) The pedigree of family PS1 shows genotypes at mutated loci (phased as displayed) of CARD14 (c.349G>A; upper) and SLC26A11 (c.365A>G; lower). The unaffected woman with an asterisk recently developed psoriasis at 83 years of age. The affected male labeled GEN001 provided skin biopsies of uninvolved and involved (psoriatic plaque) skin used for this study. (C) The pedigree of 17q25-linked Taiwanese psoriasis-affected family shows genotypes of the c.349+5G>A mutation in family members. Black-filled symbols indicate classical psoriasis. Gray-filled symbols indicate mild skin manifestation of psoriasis. Question marks indicate unknown disease status. (D) Both familial CARD14 mutations are located within the consensus splice donor sequence of exon 3. Chromatograms obtained after resequencing of this splice donor sequence in DNA of an affected member of each family are shown. The exon-intron junction is indicated by the vertical black line. The two mutations are boxed in red.
Figure 2
Figure 2
Detection of a De Novo CARD14 Mutation in an Individual with Pediatric Pustular Psoriasis and Conservation of Mutated Nucleotides (A) Child 2192, who has pustular psoriasis, before treatment. Most of the body is covered with lesions. (B) Sequence traces for 2192 and her parents revealing a de novo CARD14 mutation, c.413A>C (p.Glu138Ala). (C) The pedigree of individual 2192 shows parental genotypes for de novo mutation c.413A>C (p.Glu138Ala). (D) Alignment of DNA sequences from the indicated species is shown for the segments of CARD14 exon 3, intron 3, and exon 4 harboring the CARD14 mutations described here. The mutations are shown in red and are marked with asterisks. DNA and protein sequences were downloaded from the UCSC Genome Browser and were aligned with ClustalW2. The genome builds used for each species are as follows: hg19 (human), panTro2 (chimp), rheMac2 (rhesus), mm9 (mouse), bosTau4 (cow), canFam2 (dog), monDom5 (opossum), fr2 (fugu), gasAcu1 (stickleback), and oryLat2 (medaka).
Figure 3
Figure 3
Familial CARD14 Mutations Alter Splicing of Exon 3 (A) The CARD14 exon 3 minigene constructs are wild-type, c.349G>A (mutation in the northern European PS1 family), and c.349+5G>A (mutation in the Taiwanese psoriasis-affected family). The vertical line indicates the junction of exon 3 and the intron of CARD14. The following abbreviation is used: RSV, Rous sarcoma virus promoter. (B) Results of agarose gel electrophoresis after transfection of minigenes and isolation of cDNA. Mutant minigene PCR products were 60–70 bp larger than those of the wild-type construct. The following abbreviations are used: Non-tx, nontransfected; Vector, RHCglo vector alone; and WT, wild-type minigene. c.349G>A and c.349+5G>A are the mutant minigenes. (C) Results of sequencing minigenes. Minigene c.349+5G>A is shown. Both mutations altered splicing of exon 3 and led to the addition of 66 bp from intron 3 and splicing to exon 4 at a cryptic splice donor site (AG/GTGCCC). The following abbreviation is used: sTN1, chicken skeletal troponin I (RHCglo23 downstream gene fragment). (D) Consequence of altered splicing on CARD14.
Figure 4
Figure 4
Location of CARD14 Alterations and Their Effect on Transcriptional Activation (A) The location of the familial alterations and the de novo substitution in CARD14 are shown relative to the key protein domains. The two familial alterations are shown by blue triangles; the pustular-psoriasis alteration is shown by the purple triangle. (B) NF-kB activation levels measured in HEK 293 cells transfected with one of four options: (1) CARD14sh alone, (2) the same construct harboring one of the rare variants shown, (3) CARD14cl, or (4) a combination of two constructs from options 1–3. The change in NF-kB activity relative to the background vector was determined for each variant (y axis) (see Subjects and Methods). Every data point represents the average value of three replicates. Asterisks represent results from a two-tailed, unpaired student's t test between the indicated construct and CARD14sh. The NF-kB activity induced by cotransfection of the p.Gly117Ser substitution and wild-type CARD14sh was not statistically significant from the NF-kB activity induced by CARD14sh alone (p = 0.1) or p.Gly117Ser alone (p = 0.7). (C) HEK 001 cells were transfected with wild-type or altered (c.349G>A [p.Gly117Ser] or c.413A>C [p.Glu138Ala]) CARD14sh, and qRT-PCR was performed so that the upregulation of CCL20, IL8, SOD2, and IL36G identified by global expression profiling could be confirmed. Asterisks represent results from a two-tailed, unpaired student's t test between the indicated construct and CARD14sh. (D) Upregulation of those same transcripts was confirmed in primary keratinocytes of individual 2192 with pustular psoriasis (c.413A>C [p.Glu138Ala]). Expression in these primary keratinocytes was compared with that in two human foreskin keratinocyte samples (control 1 and control 2). For all qRT-PCR, expression levels were normalized to 18S by the 2-ΔΔCt method. For the transformation of expression levels to nondecimal integers, all expression levels were multiplied by 100,000 before being plotted on graphs. Asterisks represent results from a two-tailed, unpaired student's t test between the indicated control and the mutant (p.Glu138Ala). For (B–D), error bars represent the standard deviation of replicates, and ∗p ≤ 0.05, ∗∗p ≤ 0.01, and ∗∗∗p ≤ 0.001. The following abbreviations are used: NT, nontransfected; G117S, p.Gly117Ser; E138A, p.Glu138Ala; and Ctrl, control.
Figure 5
Figure 5
Distribution of CARD14 in Normal and Psoriatic Skin Representative images of normal and psoriatic (uninvolved and involved) skin labeled with a polyclonal antibody to the internal coiled-coil CARD14 domain that is shared by all known isoforms. (A) Normal skin and classical uninvolved and involved psoriasis skin. (B) A normal-skin negative control and uninvolved and involved affected skin from individual GEN001 from family PS1. The epidermis is the darker-stained upper band (black arrow), and the dermis is the paler region below. The black line denotes the dermoepidermal junction; lesional skin is cut on a slight cross section, and the dermis is evident as islands projecting upwards into the epidermis. The scale bar represents 100 μm.
Figure 6
Figure 6
Proposed Model of Psoriasis Pathogenesis in the Presence of Psoriasis-Specific CARD14 Alterations After an inflammatory trigger, alterations in CARD14 induce activation of NF-kB. This leads to the transcription of many genes, including key chemokines such as CCL20, IL8, and IL36G, implicated in psoriasis. The proteins encoded by these transcripts can recruit immune cells involved in disease pathogenesis. Those cells, in turn, produce cytokines and chemokines that cause inflammation and lead to further keratinocyte activation and epidermal hyperplasia (see Discussion). Other proteins in the NF-kB pathway have been previously implicated in psoriasis and might be important in CARD14 signaling to NF-kB. These proteins include A20, TNIP1, and Act1, and these, in turn, implicate TRAF2, TRAF3, and TRAF6. IL36RN, recently found to be mutated in pustular psoriasis, might also play a role in this pathway by inhibiting IL36γ-induced immune cell activation. All of these events contribute to this vicious cycle of inflammation and acanthosis seen in psoriasis.
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References

    1. Lowes M.A., Bowcock A.M., Krueger J.G. Pathogenesis and therapy of psoriasis. Nature. 2007;445:866–873. - PubMed
    1. Nograles K.E., Brasington R.D., Bowcock A.M. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat. Clin. Pract. Rheumatol. 2009;5:83–91. - PMC - PubMed
    1. Capon F., Bijlmakers M.J., Wolf N., Quaranta M., Huffmeier U., Allen M., Timms K., Abkevich V., Gutin A., Smith R. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum. Mol. Genet. 2008;17:1938–1945. - PMC - PubMed
    1. Cargill M., Schrodi S.J., Chang M., Garcia V.E., Brandon R., Callis K.P., Matsunami N., Ardlie K.G., Civello D., Catanese J.J. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 2007;80:273–290. - PMC - PubMed
    1. Ellinghaus E., Ellinghaus D., Stuart P.E., Nair R.P., Debrus S., Raelson J.V., Belouchi M., Fournier H., Reinhard C., Ding J. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat. Genet. 2010;42:991–995. - PMC - PubMed

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