CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts

Abstract

Summary Background Rare highly penetrant gain of function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs. Objectives To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and expand knowledge of CARD14 variants in the European population. Methods CARD14 coding exons were re-sequenced in psoriasis cases and controls from Tunisia and Europe including included sixteen European cases with generalized pustular psoriasis (GPP). Novel variants seen in cases were evaluated for their effect upon NF-kb signalling. Results Rare variants in CARD14 were significantly enriched in Tunisian cases compared to controls. Three were collectively found in 5% of Tunisian cases and all affected the N terminal region of the protein harbouring its CARD or coiled-coil domain. These variants were: c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-kb activity in a similar manner to previously described psoriasis-associated mutations. p.Arg69Trp led to seven fold down-regulation of NF-kb activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9 which encodes part of the coiled-coil domain. No GPP cases harboured an IL36RN mutation, but one out of 16 GPP cases with a family history of PV harboured a c.1805C>T (p.Ser602Leu) mutation. Conclusions These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.

CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis

“…Since then, several studies have reported associations of CARD14 variants with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and palmoplantar pustular psoriasis (Ammar et al, 2013(Ammar et al, , 2016Eskin-Schwartz et al, 2016;Feng et al, 2016;Gonzalez-Lara et al, 2013;Inoue et al, 2016;Korber et al, 2013;Mossner et al, 2015;Qin et al, 2014;Sugiura et al, 2014Sugiura et al, , 2015Zhu et al, 2016). Furthermore, CARD14 variants have also been associated with pityriasis rubra pilaris, a distinct inflammatory skin disease characterized by keratotic follicular papules and salmon-colored erythematous plaques (Eytan et al, 2014;Fuchs-Telem et al, 2012;Has et al, 2016;Inoue et al, 2016;Li et al, 2015).…”

“…However, not all CARD14 variants that have been identified in patients with psoriasis and pityriasis rubra pilaris lead to excessive NF-kB activation. For instance, the variant p.Arg69Trp reduces NF-kB activation sevenfold compared with wild-type CARD14 (Ammar et al, 2016). These ambiguous effects on NF-kB suggest that CARD14 could be involved in additional signaling pathways or that basal NF-kB levels might be crucial to preserve skin homeostasis.…”

“…Dectin-1, like other immune receptors (e.g., T cell receptor, B cell receptor, and NKG2D), employs immunoreceptor tyrosine-based activation motifs (ITAMs) to initiate downstream signaling via Src kinases (Thome, 2008). In T cells, Src kinase activity eventually leads to the activation of PKCq, which in turn phosphorylates and activates CARD11 (Jordan et al, 2012a;Mossner et al, 2015;Sugiura et al, 2014;Zhu et al, 2016) p.Arg179His 4 CC PsV/PPP 1.38 (Jordan et al, 2012a;Mossner et al, 2015) p.Val191Leu 4 CC PsV 1.02 (Jordan et al, 2012a) p.Glu197Lys 4 CC PPP/PsV/PsA 1.667 (Ammar et al, 2016;Mossner et al, 2015) p.Ser200Asn 4 CC PsV/GPP/PPP 0.67 (Ammar et al, 2016;Jordan et al, 2012a;Korber et al, 2013;Mossner et al, 2015) p.Leu209Pro 4 CC PsV 0.785 (Ammar et al, 2016) p.Ala216Thr 4 CC PsV 0.575 (Ammar et al, 2016;Qin et al, 2014;Zhu et al, 2016) p.Asp285Gly 6 None PsV 1.14 (Jordan et al, 2012a) p.Met338Val 7 CC PsV 0.914 (Ammar et al, 2016) p.Thr420Ala 9 none PsV 0.663 (Ammar et al, 2016) c.1356þ5G>A 9 CC PsV ND (Ammar et al, 2016) p.Thr591Met 13 PDZ PsV ND (Qin et al, 2014) p.Ile593 Asn 13 PDZ PsV 1.30 Jordan et al (2012a) p.Ser602Leu 13 PDZ PsV/GPP/PPP 1.196 (Ammar et al, 2016) p.Arg682Trp 15 SH3 PsV/GPP 0.95 (Jordan et al, 2012a;Qin et al, 2014) p.Gly714Ser 15 SH3 PsV 1.02 (Jordan et al, 2012a) p.Arg820Trp 18 GUK PsV/PsA ND (Feng et al, 2016;Gonzalez-Lara et al, 2013;Jordan et al, 2012a;Sugiura et al, 2015) p.Asp973Glu 21 GUK PsV ND (Jordan et al, 2012a) Details on the location of the mutations, their disease occurrence, and their effect on NF-kB activation is shown. The exon sequence was determined using transcript CARD14-201 (ENST00000344227 …”

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations

“…The skin disease in patients with CARD14 mutations can be limited or generalized. Autosomal dominant or sporadic gain-of-function mutations in the CARD14 gene cause GPP (101), familial pityriasis rubra pilaris (PRP) (102), psoriatic arthritis (PA) (103), PPP (104), and even pustular psoriasis suggesting a large disease severity spectrum. Fever and other systemic manifestations are generally not present but can occur with superinfections of the skin.…”

“…One Tunisian patient was reported with a c.1356+5G>A splice alteration which is predicted to lead to the skipping of exon 9, which encodes part of the coiled-coil domain (105). Mutations in CARD14 , including p.Glu138del and p.Leu156Pro, have been associated with autosomal-dominant pityriasis rubra pilaris, which is phenotypically related to psoriasis (102). …”