Abolished InsP3R2 function inhibits sweat secretion in both humans and mice

There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweatingis a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat( anhidrosis) results in heat intolerancethat may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineousfamily with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP3R2 and abrogates Ca2+ release from the endoplasmic reticulum, which suggests that intracellular Ca2+ release by InsP3R2 in clear cells of the sweat glandsis important for eccrine sweatproduction. Itpr2–/– mice exhibited a marked reduction in sweatsecretion, and evaluation of sweat glandsfrom Itpr2–/– animals revealed a decrease in Ca2+ response compared with controls. Together, our data indicate that loss of InsP3R2-mediated Ca2+ release causes isolated anhidrosisin humans and suggest that specific InsP3R inhibitors have the potential to reduce sweatproduction in hyperhidrosis.