[HTML][HTML] Interleukin-36–receptor antagonist deficiency and generalized pustular psoriasis

S Marrakchi, P Guigue, BR Renshaw… - … England Journal of …, 2011 - Mass Medical Soc
S Marrakchi, P Guigue, BR Renshaw, A Puel, XY Pei, S Fraitag, J Zribi, E Bal, C Cluzeau
New England Journal of Medicine, 2011Mass Medical Soc
Background Generalized pustular psoriasis is a life-threatening disease of unknown cause.
It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and
disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive
protein, which may be associated with plaque-type psoriasis. Methods We performed
homozygosity mapping and direct sequencing in nine Tunisian multiplex families with
autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on …
Background
Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis.
Methods
We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function.
Results
We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36–receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor–like 2 (interleukin-1 receptor–related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients.
Conclusions
Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.)
The New England Journal Of Medicine