The genetic basis for most patients with pustular skin disease remains elusive
The genetic basis for most patients with pustular skin disease remains elusive
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DOI：
10.1111/bjd.15867
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发表时间：
2018-03-01
影响因子：
10.3
通讯作者：
Hueffmeier, U.
中科院分区：
文献类型：
--
作者：
Mossner, R.;Wilsmann-Theis, D.;Hueffmeier, U.
背景基因IL 36 RN、CARD 14和AP 1 S3的罕见变异已被鉴定为引起或促成脓疱性皮肤病，主要是泛发性脓疱性银屑病（GPP）.ObjectivesTo更好地了解这些基因的疾病相关性，我们筛选了脓疱性皮肤病患者[主要是GPP和掌跖脓疱性银屑病（PPP）]的这三个基因的编码变化。方法对67例GPP、2例急性泛发性外展性脓疱病和4例Hallopeau连续性肢端皮炎患者的IL 36 RN、CARD 14和AP 1 S3基因外显子进行测序。我们筛选了IL 36 RN和AP 1 S3的基因内拷贝数变异，并筛选了258名PPP患者的AP 1 S3编码变化。分析了11名杂合子IL 36 RN突变携带者的第二个非编码IL 36 RN突变。在GPP cohol.ResultsThe大多数患者（GPP，64%）没有携带任何三个基因的罕见变异的基因型-表型相关性进行了评估。双等位基因和单等位基因IL 36 RN突变分别在15例和5例GPP患者中鉴定。在杂合子携带者中未发现非编码罕见IL 36 RN变异。在IL 36 RN突变携带者中观察到的唯一显著的基因型-表型相关性是疾病发作时的早期年龄。额外的罕见的CARD 14或AP 1 S3变异体中确定了15%的IL 36 RN突变carriers.ConclusionsThe识别IL 36 RN突变携带者窝藏额外的罕见变异CARD 14或AP 1 S3表明脓疱性银屑病的遗传更复杂的模式。我们的研究结果表明，在杂合子IL 36 RN突变携带者中，除了IL 36 RN之外，还有其他致病遗传因素。基因IL 36 RN、CARD 14和AP 1 S3与脓疱性皮肤病有关，其中IL 36 RN具有主要作用。大多数研究分别分析了不同基因的变异。脓疱性皮肤病患者的重要亚群在IL 36 RN中携带单个杂合突变，这一变异是否以及如何导致疾病尚不清楚。总的来说，15%的泛发性脓疱性银屑病（GPP）患者携带IL 36 RN突变，携带CARD 14或AP 1 S3变异，为复杂的遗传提供了证据。64%的GPP患者缺乏致病/致病变异，这表明其他尚未确定的基因也发挥了作用。基因型-表型相关性没有显示出显著的相关性，除了IL 36 RN突变的存在与发病年龄。这项对三个基因的研究提供了证据，证明GPP的遗传比以前理解的更复杂。已知基因在GPP中的作用相当有限，因为几乎三分之二的患者不携带任何这些基因的变体。在掌跖脓疱型银屑病中，非携带者的百分比甚至更低。进一步的遗传学研究将揭示疾病的发病机制，并为使用/开发更具体的治疗方法提供基础。Br J Dermatol 2018; 178：589-590回复这篇文章
BackgroundRare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).ObjectivesTo better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.MethodsCoding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort.ResultsThe majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers.ConclusionsThe identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.What's already known about this topic?The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role. Most studies have analysed variants in different genes separately. Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing.What does this study add?Intragenic copy-number variants or noncoding mutations in carriers of single IL36RN mutations were not found. In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance. Lack of causal /disease-contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes. Genotype-phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset.What is the translational message?This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood. The role of known genes in GPP is rather limited, as almost two-thirds of patients do not carry a variant in any of these genes. In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower. Further genetic studies will reveal the diseases' pathogenesis and provide a basis to use/develop more specific treatments.Linked Comment:Capon. Br J Dermatol 2018; 178:589-590 Respond to this article