title: Activating CARD14 Mutations Are Associated with Generalized Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis Vulgaris.
abstract: Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Dorottya M
authors.initials: DM
authors.lastname: Berki
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Hospital Sultanah Aminah, Johor Bahru, Malaysia.
authors.forename: Siew-Eng
authors.initials: SE
authors.lastname: Choon
authors.affiliation: Department of Dermatology, University of Glasgow, Glasgow, UK.
authors.forename: A
authors.initials: A
authors.lastname: David Burden
authors.affiliation: Department of Dermatology, University of Manchester, Manchester, UK.
authors.forename: Christopher E M
authors.initials: CEM
authors.lastname: Griffiths
authors.affiliation: Department of Dermatology, Zurich University Hospital, Zurich, Switzerland.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Navarini
authors.affiliation: National Skin Centre, Singapore, Singapore.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland; Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.affiliation: Department of Dermatology, Venereology and Allergic Disease, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Department of Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogo
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Petrof
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Satveer K
authors.initials: SK
authors.lastname: Mahil
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Duckworth
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Allen
authors.affiliation: Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Benevento, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Vito
authors.affiliation: Queen Mary, University of London, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: McGrath
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK. Electronic address: francesca.capon@kcl.ac.uk.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.affiliation: St John's Institute of Dermatology, King's College London, London, UK. Electronic address: jonathan.barker@kcl.ac.uk.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D055503:Protein Multimerization; D011565:Psoriasis / Q000209:etiology / Q000235:genetics*; D012008:Recurrence
chemical_list: D053468:CARD Signaling Adaptor Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C426243:CARD14 protein, human; D006162:Guanylate Cyclase