Mutations in IL36RN/IL1F5 Are Associated with the Severe Episodic Inflammatory Skin Disease Known as Generalized Pustular Psoriasis
Mutations in IL36RN/IL1F5 Are Associated with the Severe Episodic Inflammatory Skin Disease Known as Generalized Pustular Psoriasis
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DOI：
10.1016/j.ajhg.2011.07.022
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发表时间：
2011-09-09
影响因子：
9.8
通讯作者：
Barker, Jonathan N.
中科院分区：
文献类型：
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作者：
Onoufriadis, Alexandros;Simpson, Michael A.;Barker, Jonathan N.
泛发性脓疱型银屑病（Generalized pustular psoriasis，GPP）是银屑病的一种罕见的临床变异型，具有潜在的致死性，其特征为形成无菌皮肤脓疱、嗜中性粒细胞增多、发热和全身炎症。我们对五个诊断为GPP的无关个体的外显子组进行了测序。非同义，剪接位点，插入和缺失的变体与估计的人口频率的T（p.Ser113Leu）错义取代IL 36 RN被确定在两个人，与第三个主题被发现是一个复合杂合子c.338C>T（p.Ser113Leu）和c.142C>T（p.Arg48Trp）错义取代。IL 36 RN（以前称为IL 1F 5）编码IL-1家族受体拮抗剂，其对抗IL-36 A和IL-36 G先天性细胞因子的活性。同源性搜索显示，GPP突变改变了进化上保守的残基。c.338C>T（p.Ser113Leu）变体的纯合性与用IL 36 A离体刺激后升高的促炎反应相关。这些发现表明作为GPP的遗传基础的IL 36 RN的功能丧失，并且在这种严重的偶发性炎性疾病中涉及先天免疫失调，从而突出了IL-1信号传导作为治疗干预的潜在靶标。
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 proinflamrnatory 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.