Dataset Information

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

ABSTRACT: 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.To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population.CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-?B signalling.Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain 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-?B activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-?B 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 cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14.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.

SUBMITTER: Ammar M

PROVIDER: S-EPMC5444086 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Ammar M M Jordan C T CT Cao L L Lim E E Bouchlaka Souissi C C Jrad A A Omrane I I Kouidhi S S Zaraa I I Anbunathan H H Mokni M M Doss N N Guttman-Yassky E E El Gaaied A B AB Menter A A Bowcock A M AM

The British journal of dermatology 20151117 2

<h4>Background</h4>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.<h4>Objectives</h4>To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population.<h4>Methods</h4>CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia a ...[more]

PMID: 26358359

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Project description:Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding an NF-kB activator within skin epidermis, account for PSORS2. Here we describe fifteen additional rare, missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There was an excess of rare variants within CARD14 in cases versus controls (burden test p-value = 0.0015). Some variants were only seen in a single case and included putative pathogenic mutations (c.424G>A [p.Glu142Lys], c.425A>G [p.Glu142Gly]) and the generalized pustular psoriasis mutation, c.413A>C (p.Glu138Ala), that lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities, with putative pathogenic variants leading to levels >2.5-fold higher than wildtype CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with TNF-a to achieve significant increases in NF-kB levels. Transcriptome profiling of wildtype and variant CARD14 transfectants in keratinocytes differentiated likely pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped and meta-analysis revealed association of psoriasis with rs11652075 (c.2458C>T/p.Arg820Trp; p-value = 2.1x10-6). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. Keratinocytes were transfected with wildtype Cardsh or one of 16 Card14 mutations (17 total samples). The cells were collected and RNA extracted to determine the effect of these mutations compared to wildtype Card14. No replicates are included.

Dataset Information

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

Publications

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

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