Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Sep 9;89(3):432-7.
doi: 10.1016/j.ajhg.2011.07.022. Epub 2011 Aug 11.

Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis

Alexandros Onoufriadis  1 , Michael A Simpson, Andrew E Pink, Paola Di Meglio, Catherine H Smith, Venu Pullabhatla, Jo Knight, Sarah L Spain, Frank O Nestle, A David Burden, Francesca Capon, Richard C Trembath, Jonathan N Barker
Affiliations

Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis

Alexandros Onoufriadis et al. Am J Hum Genet. .

Abstract

Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Clinical Features of Generalized Pustular Psoriasis (A) Individual GPP-02 II:1. Note extensive plaques of erythema with superimposed pustules on the arm. (B) Individual GPP-01 II:5. Note erythematous, intensely inflamed skin with active pustulation and desquamation on the buttocks. (C) Individual GPP-03 II:2. Note widespread, healing erythematous plaques following active pustulation on the legs.
Figure 2
Figure 2
Mutation and Segregation Analysis (A) Pedigrees and mutation status of three GPP kindreds in whom mutations were identified in IL36RN. (B) Sequence chromatograms of the c.338C>T (p.Ser113Leu) and c.142C>T (p.Arg48Trp) mutations.
Figure 3
Figure 3
Location of the Two Identified Mutations (A) Location of the two identified mutations with respect to the genomic organization of IL36RN (upper panel) and IL36RN (lower panel). (B) Locations of the c.142C>T (p.Arg48Trp) and c.338C>T (p.Ser113Leu) mutations with respect to the three-dimensional structure of IL36RN, including the loop domains and critical residues that mediate receptor interaction.
Figure 4
Figure 4
Analysis of Case and Control PBMCs, after Ex Vivo Stimulation with IL-36A (A) The induction of IL1A, IL6, and IL8 mRNA was assessed by real-time PCR, with the RPLPO transcript used as an endogenous control. Data are plotted as the mean, and error bars represent the SEM of duplicate stimulations with the expression level of the unstimulated sample set as a baseline value. CTR, control. (B) The concentration of IL-1α, IL-6, IL-8, and TNF was assayed in the PBMC culture medium. Data are plotted as the mean, and error bars represent the SEM of duplicate stimulations. All significance values were calculated via a one-way ANOVA test, followed by a Bonferroni posttest. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. CTR, control.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Griffiths C.E.M., Barker J.N.W.N. Psoriasis. In: Burns T., Breathnach S., Cox N., Griffiths C.E.M., editors. Rook's Textbook of Dermatology. Wiley-Blackwell; Chichester, England: 2010. pp. 20.1–20.60.
    1. Simpson M.A., Irving M.D., Asilmaz E., Gray M.J., Dafou D., Elmslie F.V., Mansour S., Holder S.E., Brain C.E., Burton B.K. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 2011;43:303–305. - PubMed
    1. Strange A., Capon F., Spencer C.C., Knight J., Weale M.E., Allen M.H., Barton A., Band G., Bellenguez C., Bergboer J.G., Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2 A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 2010;42:985–990. - PMC - PubMed
    1. Li H., Handsaker B., Wysoker A., Fennell T., Ruan J., Homer N., Marth G., Abecasis G., Durbin R., 1000 Genome Project Data Processing Subgroup The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. - PMC - PubMed
    1. Wang K., Li M., Hakonarson H. ANNOVAR: Functional annotation of genetic variants from next-generation sequencing data. Nucleic Acids Res. 2010;38:164. - PMC - PubMed

Publication types