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IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases
- Source :
- Journal of Investigative Dermatology. 136:1811-1819
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
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.
- Subjects :
- Adult
Male
0301 basic medicine
Genotype
Pustular Eruption
Dermatology
Gene mutation
Biology
Compound heterozygosity
Risk Assessment
Biochemistry
03 medical and health sciences
Psoriasis
medicine
Humans
Child
Molecular Biology
Genetic Association Studies
Interleukins
Acrodermatitis
Wild type
Cell Biology
Prognosis
medicine.disease
Phenotype
030104 developmental biology
Gene Expression Regulation
Interleukin 36 receptor antagonist
Child, Preschool
Mutation
Immunology
Disease Progression
Generalized pustular psoriasis
Female
Subjects
Details
- ISSN :
- 0022202X
- Volume :
- 136
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology
- Accession number :
- edsair.doi.dedup.....01b440cb0856bb45ebd55c4e2dd44499