Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome
| Autor: | Weilong Zhong, Jie Zhang, Li Tang, Xianning Zhang, Xu Cao, Mingyang Lee, Linghan Hu, Xiuli Wang, Jiahui Zhao, Lina Duo, Yong Yang, Quan Chen, Huijun Wang, Cheng Feng, Zhimiao Lin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty TRPV3 Adolescent Genotyping Techniques TRPV Cation Channels Dermatology Biology Biochemistry 03 medical and health sciences Transient receptor potential channel Basal (phylogenetics) 0302 clinical medicine Channelopathy Keratoderma Palmoplantar Internal medicine medicine Homomeric Humans Child Medical History Taking Molecular Biology Genetic Association Studies HEK 293 cells Wild type Cell Biology Syndrome medicine.disease 030104 developmental biology Palmoplantar keratoderma Endocrinology HEK293 Cells 030220 oncology & carcinogenesis Gain of Function Mutation Female Hair Diseases |
| Zdroj: | The Journal of investigative dermatology. 141(3) |
| ISSN: | 1523-1747 |
| Popis: | We have previously shown that gain-of-function variations in transient receptor potential vanilloid-3 (TRPV3) underlay Olmsted syndrome, a rare hyperkeratotic skin channelopathy. In this study, we attempt to establish a genotype‒phenotype correlation in Olmsted syndrome, which has been unclear owing to the rarity and heterogeneity of the condition. We identified five previously unreported TRPV3 variations (R416Q, R416W, L655P, W692S, and L694P) and three recurrent variations (G568D, G568V, and L673F) in nine unrelated patients. Seven variants were expressed in human embryonic kidney 293 cells, and channel behavior was characterized electrophysiologically, with results compared with the clinical severity. These variant TRPV3 channels, in either homomeric or heteromeric form, exhibited differentially elevated basal open probability, increased voltage sensitivity, and cytotoxicity. Functional changes were particularly pronounced in variants corresponding to severer Olmsted syndrome (e.g., L673F and W692S) but not in mild Olmsted syndrome variants (e.g., R416Q). Interestingly, the extent of functional rescue by wild-type TRPV3 in vitro was also consistent with the clinical severity of the variants. These findings, in combination with all reported cases, indicate a preliminary genotype‒phenotype correlation, that is, variations in the S4‒S5 linker and transient receptor potential domain of TRPV3 significantly enhance channel function, causing severe phenotype, whereas other variations appear to exert milder effects on channel function and disease phenotype. |
| Databáze: | OpenAIRE |
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