Mutations in IL36RN/IL1F5 Are Associated with the Severe Episodic Inflammatory Skin Disease Known as Generalized Pustular Psoriasis

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....

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Bibliographic Details
Published in:American journal of human genetics 2011-09, Vol.89 (3), p.432-437
Main Authors: Onoufriadis, Alexandros, Simpson, Michael A., Pink, Andrew E., Di Meglio, Paola, Smith, Catherine H., Pullabhatla, Venu, Knight, Jo, Spain, Sarah L., Nestle, Frank O., Burden, A. David, Capon, Francesca, Trembath, Richard C., Barker, Jonathan N.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Bullous diseases of the skin
Child
Child, Preschool
Cytokines
Dermatology
Female
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genetic Predisposition to Disease - genetics
Genetics
Genetics of eukaryotes. Biological and molecular evolution
Humans
Immunity, Innate - genetics
Immunity, Innate - immunology
Interleukins - genetics
Interleukins - immunology
Interleukins - metabolism
Male
Medical genetics
Medical sciences
Middle Aged
Models, Molecular
Molecular and cellular biology
Mutation
Mutation, Missense - genetics
Pedigree
Psoriasis
Psoriasis - genetics
Psoriasis - immunology
Sequence Analysis, DNA
Signal transduction
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Summary: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 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.
ISSN:0002-9297
1537-6605
1537-6605
DOI:10.1016/j.ajhg.2011.07.022