title: CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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)-κB signalling.
  
  
  RESULTS
  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-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB 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.
  
  
  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.
authors.affiliation: Laboratoire de Génétique d'Immunologie et de Pathologies Humaines, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: Ammar
authors.affiliation: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, U.S.A.
authors.forename: C T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, U.S.A.
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.affiliation: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, U.S.A.
authors.forename: E
authors.initials: E
authors.lastname: Lim
authors.affiliation: Laboratoire de Génétique d'Immunologie et de Pathologies Humaines, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: C
authors.initials: C
authors.lastname: Bouchlaka Souissi
authors.affiliation: Unité de Recherche de Physiologie des Agressions: Etudes Métaboliques et Endocriniennes, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: A
authors.initials: A
authors.lastname: Jrad
authors.affiliation: Laboratoire de Génétique d'Immunologie et de Pathologies Humaines, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: I
authors.initials: I
authors.lastname: Omrane
authors.affiliation: Laboratoire de Génétique d'Immunologie et de Pathologies Humaines, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: S
authors.initials: S
authors.lastname: Kouidhi
authors.affiliation: Department of Dermatology, La Rabta Hospital of Tunis, Tunis, Tunisia.
authors.forename: I
authors.initials: I
authors.lastname: Zaraa
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, SW3 6LY, U.K.
authors.forename: H
authors.initials: H
authors.lastname: Anbunathan
authors.affiliation: Department of Dermatology, La Rabta Hospital of Tunis, Tunis, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: Mokni
authors.affiliation: Department of Dermatology, Military Hospital of Tunis, Tunis, Tunisia.
authors.forename: N
authors.initials: N
authors.lastname: Doss
authors.affiliation: Department of Dermatology and the Immunology Institute, Icahn School of Medicine at the Mount Sinai Medical Center, NY, U.S.A.
authors.forename: E
authors.initials: E
authors.lastname: Guttman-Yassky
authors.affiliation: Laboratoire de Génétique d'Immunologie et de Pathologies Humaines, Faculté des Sciences de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: A B
authors.initials: AB
authors.lastname: El Gaaied
authors.affiliation: Division of Dermatology, Baylor University Medical Center, Junius St, Suite 145, Dallas 3900, TX, 75246, U.S.A.
authors.forename: A
authors.initials: A
authors.lastname: Menter
authors.affiliation: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, U.S.A.|National Heart and Lung Institute, Imperial College London, London, SW3 6LY, U.K.
authors.forename: A M
authors.initials: AM
authors.lastname: Bowcock
mesh_terms: D000328:Adult; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D011565:Psoriasis / Q000208:ethnology / Q000235:genetics*; D015398:Signal Transduction; D014416:Tunisia; D015854:Up-Regulation / Q000235:genetics; D044465:White People / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
chemical_list: D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C426243:CARD14 protein, human; D006162:Guanylate Cyclase