Olmsted综合征（OS）是一种以掌跖及腔口周围皮肤严重角化伴剧烈瘙痒为特征的常显遗传病。我们研究组近期通过外显子组测序及电生理学方法确定OS为TRPV3基因功能增强型突变所致。然而，OS的临床表现严重程度是否与基因突变位点相关？OS皮疹为何仅限于掌跖及腔口周围？这些都是亟待解决的问题。我们在前期工作的基础上，提出假设：OS临床严重程度可能与TRPV3突变后通道活性改变程度相关；OS皮损部位特异性可能与TRPV3在不同部位皮肤中差异性表达，或者与突变体通道的温度特性改变相关。本研究拟采用突变体与野生型共表达方法比较不同TRPV3突变体通道活性及通道温度特性改变情况，同时研究TRPV3在OS患者以及正常人不同部位皮肤组织中的表达情况，深入阐明OS的发病机制及临床表型与基因型的关系，从而揭示部分关键性氨基酸位点在TRPV3通道功能中的作用，为开发靶点特异性TRPV3阻断剂奠定基础。

Olmsted syndrome (OS) is an autosomal dominant inherited disease characterized by severe periorificial and palmoplantar keratoderma with intolerant pruritus. We have recently identified mutations in TRPV3 as a cause of OS by exome sequencing. The mutations found in OS exert a gain-of-function effect, which was demonstrated in our previous electrophysiological studies. However, the exact pathogenesis of OS is not definitely understood, and the relationship betweent the phenotype of OS and TRPV3 genotype is unclear. Based on our previous studies, a correlation between the severity of clinical manifestations of OS and the extent of mutation effect on TRPV3 channel activity was assumed. The predilection sites of OS lesions were postulated to be related either with the variability of TRPV3 expression in different sites of skin tissue, or with the altered temperature properties of the TRPV3 mutants. In the present studies, the mutations detected in OS patients will be co-expressed with wild type TRPV3 in HEK293 cells, followed by electrophysiological studies and dynamic calcium imaging for intracellular calcium ion measurement. The cytotoxic effect and the temperature properties of the HEK293 cells co-expressing mutants and wild type TRPV3 will also be evaluated. Meanwhile, the expression variability of TRPV3 in different sites of skin tissues from normal controls and OS patients will be studied by real-time PCR and immunofluorescence. Our studies will further reveal the pathogenesis of OS and the relationship between the phenotype and TRPV3 genotype. The　function of several cirtical amino acids of TRPV3 will be unraveled, which may shed a light in the development of blocking drugs specially targeting TRPV3.