IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases
IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases
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DOI：
10.1016/j.jid.2016.04.038
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发表时间：
2016-09-01
影响因子：
6.5
通讯作者：
Smahi, Asma
中科院分区：
文献类型：
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作者：
Tauber, Marie;Bal, Elodie;Smahi, Asma
纯合子或复合杂合子IL 36 RN基因突变是银屑病相关脓疱性皮疹发病机制的基础，包括泛发性脓疱性银屑病、掌跖脓疱性银屑病、Hallopeau连续性肢端皮炎和急性泛发性外剥性脓疱性皮疹。我们在家族性泛发性脓疱性银屑病患者中发现了两种未报道的IL 36 RN纯合突变（c.41C>A/p.Ser14X和c.420_426del/p.Gly141MetfsX29）。我们通过使用定点突变和在HEK 293 T细胞中的表达分析了一系列IL-36 RN突变对IL-36受体拮抗剂蛋白的影响。这使我们能够区分无效突变与完全缺乏IL-36受体拮抗剂（两个先前未报道的突变，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，和c.227C>T/p.Pro76Leu）（c.95A>G/p.His32Arg，c.142C>T/p.Arg48Trp，和c.308C>T/p.Ser113Leu）或不变（c.304C>T/p.Arg102Trp和c.104A>G/p.Lys35Arg）蛋白表达。测量突变对抑制NF-κ B通路的IL-36依赖性活化的能力的影响的功能测定显示无效突变的完全功能损害，而对于被认为是亚型的其他突变观察到部分或没有损害。最后，无效突变与严重的临床表型（泛发性脓疱性银屑病，急性泛发性外发性脓疱性皮疹），而亚型突变被确定在本地（掌跖脓疱性银屑病，连续性Hallopeau肢端皮炎）和泛发性变异。这些结果为IL-36 Ra（DITRA）缺乏患者的基因型-表型相关性提供了初步依据，并提示其他因素参与了临床表达的调节。
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-kappa B 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.