Olmsted syndrome causing point mutants of TRPV3 (G568C and G568D) show defects in intracellular Ca2+-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 Ca2+-influx in response to activation by agonist (FPP). These two mutants fail to mobilise Ca2+ from intracellular stores, especially when cytosolic Ca2+ is chelated and/or in absence of extracellular Ca2+. We demonstrate that OS-mutants cause defective pH-maintenance at the lysosomes. We propose that G568C and G568D mutants most-likely act as Ca2+-leaky channels from lysosomes with different abilities. Mutations in TRPV3 at G568 position (G568C, G568D) lead to Olmested Syndrome due to abnormalities associated with maintenance of lysosomal pH and intracellular Ca2+-levels. [Display omitted] • TRPV3-Wt and TRPV3 mutants (G568C and G568D) are localized in the lysosome. • Presence of TRPV3 mutants (G568C or G568D) causes reduced lysosomes and defective lysosomal numbers. • TRPV3-Wt and TRPV3 mutants (G568C and G568D) have different intracellular Ca2+-levels and intracellular Ca2+-buffering capacity. • TRPV3 have unique capacity to sense intracellular pH and Ca2+-levels. • TRPV3-mediated lysosomal regulation is relevant for channelopathies and different lysosomal disorders. [ABSTRACT FROM AUTHOR]