Table 6_Deciphering the role of IL17RA in psoriasis and chronic mucocutaneous candidiasis: shared pathways and distinct manifestations.xlsx

IntroductionPsoriasis and chronic mucocutaneous candidiasis (CMC), although distinct in their clinical manifestations, often coexist within specific patient cohorts. Despite this intriguing clinical observation, their genetic etiologies have been studied separately, neglecting the shared inflammatory mediator, interleukin 17A-F (IL17A-F). Consequently, the immunogenetic foundations underlying these conditions have remained enigmatic.
MethodsIn this study, we analyzed the case of a 5-year-old female born to consanguineous parents who presented with concomitant psoriasis and CMC phenotypes. Utilizing whole exome and transcriptomic sequencing, we meticulously investigated the genetic underpinnings and molecular pathways underlying these complex pathologies. RNA sequencing was performed on a skin biopsy to confirm transcriptomic profiles associated with these conditions.
ResultsWe identified a novel bi-allelic variant (NM_014339.6, c.1173C>G A) within the interleukin 17 receptor type A (IL17RA) gene, resulting in a premature stop codon (p. Tyr391Ter). Despite the truncation, our investigations revealed that this variant produces a fully functional IL17RA protein. This was evident from the presence of IL17RA in the patient’s peripheral blood mononuclear cells (PBMCs) and the ability of the mutant IL17RA to dimerize with both wild-type protein and its partners IL17RC and IL17RD. Transcriptomic analysis of the skin biopsy showed a distinct psoriasis-associated signature intertwined with inflammatory pathways, including responses to fungal infections.
DiscussionThis report unveils an unprecedented genetic link serving as a common denominator for psoriasis and CMC. The novel IL17RA variant highlights the pivotal role of this receptor in the shared inflammatory pathways underlying these conditions. Our findings bridge a critical knowledge gap and provide insights into the molecular mechanisms connecting these diseases. This discovery not only advances our understanding of their pathophysiology but also lays the groundwork for personalized therapeutic strategies, heralding a new era of precision medicine for patients with intertwined psoriasis and CMC.

引言 银屑病与慢性皮肤黏膜念珠菌病（chronic mucocutaneous candidiasis, CMC）尽管临床表现迥异，却常于特定患者队列中共同出现。尽管这一有趣的临床现象已被观测到，但二者的遗传病因学研究一直各自独立开展，忽视了共享的炎症介质白细胞介素17A-F（interleukin 17A-F, IL17A-F）。因此，这两种疾病背后的免疫遗传基础至今仍不明朗。
方法 本研究对一名来自近亲婚配父母的5岁女性患者展开分析，该患者同时表现出银屑病与慢性皮肤黏膜念珠菌病表型。本研究采用全外显子组测序与转录组测序技术，对这两种复杂疾病的遗传基础与分子通路展开细致探究。此外，我们对患者的皮肤活检组织进行RNA测序，以验证与这两种疾病相关的转录组特征。
结果 本研究在白细胞介素17受体A型（interleukin 17 receptor type A, IL17RA）基因中发现了一种新型双等位基因变异（NM_014339.6, c.1173C>G A），该变异可导致提前出现终止密码子（p. Tyr391Ter）。尽管该变异会造成蛋白截短，但研究显示，此变异仍可编码具备完全功能的IL17RA蛋白。这一结论可通过以下两点得到证实：患者外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）中存在IL17RA蛋白，且突变型IL17RA能够与野生型IL17RA蛋白及其结合伴侣IL17RC、IL17RD发生二聚化。对皮肤活检组织的转录组分析显示，患者存在显著的银屑病相关特征，且该特征与包括真菌感染应答在内的炎症通路相互交织。
讨论 本研究首次揭示了银屑病与慢性皮肤黏膜念珠菌病之间的遗传关联，该关联可作为二者的共同致病基础。此次发现的新型IL17RA变异凸显了该受体在这两种疾病共享的炎症通路中的关键作用。本研究成果填补了相关领域的关键认知空白，为解析这两种疾病的关联分子机制提供了新视角。该发现不仅加深了我们对二者病理生理学的理解，更为个性化治疗策略奠定了基础，为合并银屑病与慢性皮肤黏膜念珠菌病的患者开启精准医疗的新时代。