Olmsted syndrome causing point mutants of TRPV3 (G568C and G568D) show defects in intracellular Ca-mobilization and induce lysosomal defects.

TRPV3, a non-selective cation channel known to be activated by physiological temperature, is expressed in skin and is involved in different skin functions. Point mutations in TRPV3 cause severe pathological condition, known as Olmsted Syndrome (OS). Now we demonstrate that two OS-inducing point mutations (G568C and G568D) located at the lipid-water-interface region joining TM4 with the loop4 of TRPV3 cause reduced cell size and major defects in lysosomal numbers, and distribution. We detected these two mutants in the lysosome. However, G568C and G568D mutants differ from themselves and also from Wild-type in terms of Ca-influx in response to activation by agonist (FPP). These two mutants fail to mobilise Ca from intracellular stores, especially when cytosolic Ca is chelated and/or in absence of extracellular Ca. We demonstrate that OS-mutants cause defective pH-maintenance at the lysosomes. We propose that G568C and G568D mutants most-likely act as Ca-leaky channels from lysosomes with different abilities.