Genotype-Phenotype Correlation of TRPV3-Related Olmsted Syndrome

Abstract We have previously shown that gain-of-function mutations in TRPV3 underlay Olmsted syndrome (OS), a rare hyperkeratotic skin channelopathy. Here, we attempt to establish a genotype-phenotype correlation in OS, which has been unclear due to the rarity and heterogeneity of the condition. We identified five previously unreported TRPV3 mutations (R416Q, R416W, L655P, W692S, and L694P) and three recurrent mutations (G568D, G568V, and L673F) in nine unrelated patients. These mutants were expressed in HEK293 cells and channel behavior was characterized electrophysiologically, with results compared to the clinical severity. All mutant TRPV3 channels, in either homomeric or heteromeric form, exhibited differentially elevated basal open probability, increased voltage sensitivity and cytotoxicity. These functional changes were particularly pronounced in mutants corresponding to severer OS (e.g., L673F and W692S), but not in mild OS mutants (e.g., R416Q). Interestingly, the extent of functional rescue by WT TRPV3 in vitro was also consistent with clinical severity of the mutants. These findings, in combination with all reported cases, indicate a preliminary genotype-phenotype correlation, that is, mutations in the S4-S5 linker and TRP domain of TRPV3 significantly enhance channel function, causing severe phenotype, while other mutations appear to exert milder effects on channel function and disease phenotype.