NCR2基因与sapho综合症相关性的初步探讨

Sapho syndrome (synovitis-acne-pustulosis-hyperostosis-osteomyelitis syndrome) is immune system-related chronic disease, mainly involving the skin, bones and joints. Sapho syndrome is a rare disease, the number of reported cases currently is less than 1000 worldwide, and more than 80 % of cases are from Europe, North America, Japan, Australia and other countries, in China, more than one hundred cases were reported. Maybe due to the difficulties in collecting and easy to misdiagnosis, the disease gene and mechanism of sapho syndrome is still unknown. By using whole exome sequencing, we had identified some genes were involved in the etiology of sapho syndrome, including NCR2, CD200R1, UMODL1, etc, further validation study in 60 sporadic cases revealed there were much more missense mutations in the coding region of NCR2 gene (35/60, 58.3%), suggesting NCR2 maybe is the causative gene of sapho syndrome. Based on these previous results, we designed the following assays: 1) detecting the expression level of NCR2, IL-1, IL-6, IL-23 and other cytokines of sapho cases; 2) defining the pathway of NCR2 gene in sapho by over expression and RNA interference assay in vitro; 3) constrcting NCR2 knockout mice and exploring the association between NCR2 and sapho in detail.

Sapho综合症是一种与免疫系统相关的、主要累及患者皮肤、骨和关节部位的慢性疾病，它属于罕见病，目前全球报道的例数不足1000例，以散发病例为主。虽然近几年国际上对该病的研究越来越多，但是由于易于漏诊及病例收集困难等原因，所以迄今为止一直没有发现该病的致病基因和相关通路。本研究室前期利用全外显子组测序技术对2个sapho综合症家系进行致病基因克隆研究，发现NCR2在35例患者中（35/60，58.3%）均被检测到有错义突变发生，提示NCR2基因可能是sapho综合症的致病基因。本申请将在前期研究的基础上1）筛查sapho综合症患者中NCR2蛋白的表达量，检测NCR2基因与各种炎性因子的相关性；2）构建NCR2基因的过表达与干扰载体，在细胞水平上检测NCR2基因的作用通路；3）构建NCR2基因敲除小鼠，检测NCR2基因敲除小鼠能否表现出类似于人sapho综合症样的表型，并详细探讨其作用机制。