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:BackgroundOcular cystinosis is a rare autosomal recessive disorder characterized by intralysosomal cystine accumulation in renal, ophthalmic (cornea, conjunctiva), and other organ abnormalities. Patients with ocular cystinosis are mostly asymptomatic and typically experience mild photophobia due to cystine crystals in the cornea observed accidently during a routine ocular examination. The ocular cystinosis is associated with different mutations in CTNS gene. Cysteamine therapy mostly corrects the organ abnormalities.MethodsThis study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital. The Optical Coherence Tomography (OCT) of the cornea and retinal photography were used to search cystine crystals within the corneas and conjunctiva in eight Tunisian patients. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene.ResultsThe studied patients were found to have cystine crystal limited anterior corneal stroma and the conjunctiva associated with retinal crystals accumulation. CTNS gene sequencing disclosed 7 mutations: three missense mutations (G308R, p.Q88K, and p.S139Y); one duplication (C.829dup), one framshift mutation (p.G258f), one splice site mutation (c.681 + 7delC) and a large deletion (20,327-bp deletion). Crystallographic structure analysis suggests that the novel mutation p.S139Y is buried in a first transmembrane helix closed to the lipid bilayer polar region, introducing a difference in hydrophobicity which could affect the hydrophobic interactions with the membrane lipids. The second novel mutation p.Q88K which is located in the lysosomal lumen close to the lipid membrane polar head region, introduced a basic amino acid in a region which tolerate only uncharged residue. The third missense mutation introduces a positive change in nonpolar tail region of the phospholipid bilayer membrane affecting the folding and stability of the protein in the lipid bilayer.ConclusionsOur data demonstrate that impaired transport of cystine out of lysosomes is the most common, which is obviously associated with the mutations of transmembrane domains of cystinosine resulting from a total loss of its activity.

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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