Channelopathies (Olmsted Syndrome)-causing point mutations of TRPV3 disrupt cellular thermal homeostasis in human...

TRPV3 is a thermosensitive and non-selective cation channel activated at physiological temperatures. It is abundantly expressed in skin keratinocytes, and point mutations in TRPV3 cause a rare genetic disorder, a channelopathy known as Olmsted Syndrome (OS). TRPV3-mutations that cause Olmsted Syndrome show major defects in lysosomal functions and many other cellular abnormalities, such as defects in cell adhesion, cell size and mitochondrial metabolism. In this work, we used a library of thermosensitive organelle probes to explore the sub-cellular thermal spectrum of the OS-causing TRPV3 mutant expressing cells and TRPV3-WT expressing cells in the model of a human keratinocyte cell line (HaCaT). We observe a drastic deviation in the thermal spectrum among the sub-cellular organelles in the cells expressing OS-mutants from the cells expressing WT-TRPV3 on a relative scale. Notably, cells expressing different OS-mutants display a lower temperature of the nucleus, irrespective of the position of the point mutation in TRPV3. In addition, higher temperatures of the ER, plasma membrane and lysosomes were observed, but such changes are dependent on the mutation. Our data confirm that disease-causing mutations in TRPV3 alter the "thermal spectrum" of the cells. This is the first evidence demonstrating the "genetic regulation" of thermal homeostasis at the cellular level and the involvement of TRPV3 in such function. These findings may have significance in deciphering the regulation of thermal homeostasis within the different subcellular organelles in general and demonstrate the importance of the thermosensitive ion channel TRPV3 in such a process.