摘要： Gain-of-function mutations in TRPV3 can result in Olmsted syndrome, characterized by palmoplantar and periorificial keratoderma, itch, and hair loss. The mechanisms underlying these phenotypes are unclear. Here, we engineered the first knock-in mouse model of Trpv3 by introducing a point mutation analogous to that (G568V) found in Olmsted syndrome patients. Homozygous Trpv3 knock-in (Trpv3G568V/G568V) mice exhibit sparse hair within two weeks after birth. Histologically, hair shafts in Trpv3G568V/G568V mice are twisted in the infundibulum, unable to penetrate the skin. Immunofluorescence demonstrated impaired inner root sheath cell differentiation as trichohyalin and KRT71 were diminished in mutant hair follicles. These abnormalities are consistent with the expression pattern of Trpv3, which is predominantly in the proximal region of inner root sheath as demonstrated by in situ hybridization and in a Trpv3 reporter mouse model we engineered. The hair loss phenotype is progressive, and is associated with the lack of typical telogen. After three hair cycles, Trpv3G568V/G568V mice became completely bald. Aberrantly increased proliferation and ectopic expression of epidermal markers, including KRT1 and loricrin, are characteristic of degenerating hair follicles in Trpv3G568V/G568V mice, which gradually lose stem cells, as marked by CD34, NFATc1 and KRT15, and the typical structure of a hair follicle. Findings from this study suggest that Trpv3 is an important regulator of inner root sheath keratinocyte differentiation, whereas hair loss associated with gain-of-function mutations in Trpv3 is caused by impaired proliferation and differentiation programs, leading to the exhaustion of follicular keratinocyte stem cells, and permanent disruption of the hair follicles.