课题组前期发现TYK2为麻风易感基因，深度测序显示其编码区域变异位点rs55882956与疾病的相关性最强。rs55882956位于TYK2蛋白的假激酶功能区域，蛋白结构分析发现该变异影响TYK2蛋白结构稳定性，提示其可能通过妨碍JAK-STAT信号转导,进而影响巨噬细胞、树突状细胞、NK细胞等对病原微生物的识别及杀伤，从而导致疾病的发生,目前尚缺乏实验证实。课题组已对测序所得变异位点进一步验证并明确为致病变异。后续课题组拟利用转录组测序、qPCR、免疫组化、免疫印迹等技术阐述致病变异对TYK2基因功能的影响；而后利用吗啉代反义寡核苷酸Knock-down斑马鱼探讨致病变异的致病性；同时构建突变型细胞系，检测该变异位点对JAK-STAT信号通路蛋白磷酸化水平影响，以最终阐释麻风的发病机理，为疾病风险预测、疾病干预等累积基础。

TYK2 has been identified as one of susceptibility genes of leprosy previously. Next generation sequencing has been employed to determine the rare variant rs55882956 (G/A,p.R703W), which was located in the pseudokinase domain of TYK2. This domain did not show phosphotransfer activity, but it binds ATP and the nucleotide binding stabilizes the protein. Mutation of the domain ATP-binding pocket increased basal TYK2 phosphorylation and downstream signaling.In our previous study, the result of protein structural analysis suggests that the rs55882956 has a strong destabilizing effect on the protein structure, indicating that the rare variant may be involved in pathogenesis of leprosy via influence the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal transduction pathway, but the mechanism remains unclear. To figure out that question, the rare variant rs55882956 (p.R703W) have been validated to be causal variant in 1,000 leprosy cases and 1,000 health controls by genotyping analysis. Furthermore, transcriptome sequencing,qPCR, immunochemistry, Western Blot will be conducted to clarify how the causal variant affects the function of TYK2. The mechanism of causal variant will be explored using gene knock-down Zebrafish. The phosphorylation of TYK2 and STAT will be detected in vitro methods. This study will be greatly advancing the biological understanding of leprosy as well as other mycobacteria infectious diseases.