title: IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases.
abstract: Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36-dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Tauber
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bal
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Pei
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Madrange
authors.affiliation: Department of Dermatology, CHU Oran, Oran, Algeria.
authors.forename: Amel
authors.initials: A
authors.lastname: Khelil
authors.affiliation: Department of Dermatology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Houria
authors.initials: H
authors.lastname: Sahel
authors.affiliation: Central laboratory of Biology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Akila
authors.initials: A
authors.lastname: Zenati
authors.affiliation: Central laboratory of Biology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Makrelouf
authors.affiliation: Department of Dermatology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Khaled
authors.initials: K
authors.lastname: Boubridaa
authors.affiliation: Department of Dermatology, CHU Oran, Oran, Algeria.
authors.forename: Amel
authors.initials: A
authors.lastname: Chiali
authors.affiliation: Department of Dermatology, CHU Oran, Oran, Algeria.
authors.forename: Naima
authors.initials: N
authors.lastname: Smahi
authors.affiliation: Department of Dermatology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Farida
authors.initials: F
authors.lastname: Otsmane
authors.affiliation: Department of Dermatology, CHU Bab El Oued, Bab el Oued, Alger, Algeria.
authors.forename: Bakar
authors.initials: B
authors.lastname: Bouajar
authors.affiliation: Department of Dermatology and the Laboratory of Immunology, Hedi Chaker Hospital, Sfax University, Sfax, Tunisia.
authors.forename: Slaheddine
authors.initials: S
authors.lastname: Marrakchi
authors.affiliation: Department of Dermatology and the Laboratory of Immunology, Hedi Chaker Hospital, Sfax University, Sfax, Tunisia.
authors.forename: Hamida
authors.initials: H
authors.lastname: Turki
authors.affiliation: Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourrat
authors.affiliation: Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Manuelle
authors.initials: M
authors.lastname: Viguier
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Yamina
authors.initials: Y
authors.lastname: Hamel
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France; Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Bachelez
authors.affiliation: INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France. Electronic address: asma.smahi@inserm.fr.
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011565:Psoriasis / Q000235:genetics* / Q000503:physiopathology; D018570:Risk Assessment
chemical_list: C122187:IL36RN protein, human; D007378:Interleukins